research papers on breast cancer

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Re: Non-progressive breast carcinomas detected at mammography screening: a population study—a model test or a novel test of cancer regression?

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Retraction Note: Loss of pigment epithelium-derived factor: a novel mechanism for the development of endocrine resistance in breast cancer

Receptor conversion and survival in breast cancer liver metastases.

Breast cancer liver metastases (BCLM) is a common cause of breast cancer-related death. The prognostic and predictive value of receptor expression and St Gallen classification is challenged by receptor status ...

The role of three-dimensional in vitro models in modelling the inflammatory microenvironment associated with obesity in breast cancer

Obesity is an established risk factor for breast cancer in postmenopausal women. However, the underlying biological mechanisms of how obesity contributes to breast cancer remains unclear. The inflammatory adip...

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant

The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–po...

Phenotypically sorted highly and weakly migratory triple negative breast cancer cells exhibit migratory and metastatic commensalism

Intratumor heterogeneity is a well-established hallmark of cancer that impedes cancer research, diagnosis, and treatment. Previously, we phenotypically sorted human breast cancer cells based on migratory poten...

Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study

Previous studies assessed the prognostic effect of aspirin, statins, and metformin in breast cancer (BC) patients, with inconclusive results.

Single-cell RNA reveals a tumorigenic microenvironment in the interface zone of human breast tumors

The interface zone, area around invasive carcinoma, can be thought of as the actual tissue of the tumor microenvironment with precedent alterations for tumor invasion. However, the heterogeneity and characteri...

FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer

Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not b...

Correction: Long noncoding RNA PVT1 promotes breast cancer proliferation and metastasis by binding miR-128-3p and UPF1

The original article was published in Breast Cancer Research 2021 23 :115

Host, reproductive, and lifestyle factors in relation to quantitative histologic metrics of the normal breast

Emerging data indicate that variations in quantitative epithelial and stromal tissue composition and their relative abundance in benign breast biopsies independently impact risk of future invasive breast cance...

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD), effectively shrinks tumors both in intracranial and subcutaneous ER + breast cancer models

Targeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develo...

Circulating 27-hydroxycholesterol, lipids, and steroid hormones in breast cancer risk: a nested case–control study of the Multiethnic Cohort Study

Laboratory studies have indicated that a cholesterol metabolite and selective estrogen receptor modulator, 27-hydroxycholesterol (27HC), may be important in breast cancer etiology and explain associations betw...

Publisher Correction: RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer

The original article was published in Breast Cancer Research 2023 25 :84

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~...

Examination of fully automated mammographic density measures using LIBRA and breast cancer risk in a cohort of 21,000 non-Hispanic white women

Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on a...

miR-203 drives breast cancer cell differentiation

A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher cap...

Loss of SPRY2 contributes to cancer-associated fibroblasts activation and promotes breast cancer development

The communication between tumor cells and tumor microenvironment plays a critical role in cancer development. Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and tak...

The impact of cardiovascular disease on all-cause and cancer mortality: results from a 16-year follow-up of a German breast cancer case–control study

Cardiovascular disease (CVD) is the leading cause of death worldwide. The aim of this study was to examine if CVD affects the mortality of women after a breast cancer diagnosis and population controls differen...

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in...

Deep learning applications to breast cancer detection by magnetic resonance imaging: a literature review

Deep learning analysis of radiological images has the potential to improve diagnostic accuracy of breast cancer, ultimately leading to better patient outcomes. This paper systematically reviewed the current li...

Enhancement of PD-L1-attenuated CAR-T cell function through breast cancer-associated fibroblasts-derived IL-6 signaling via STAT3/AKT pathways

Carcinoma-associated fibroblasts (CAFs) play a critical role in cancer progression and immune cell modulation. In this study, it was aimed to evaluate the roles of CAFs-derived IL-6 in doxorubicin (Dox) resist...

Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway

Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. No...

RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic act...

The Publisher Correction to this article has been published in Breast Cancer Research 2023 25 :94

Association of air pollution with postmenopausal breast cancer risk in UK Biobank

We investigated the association of several air pollution measures with postmenopausal breast cancer (BCa) risk.

Exploring breast tissue microbial composition and the association with breast cancer risk factors

Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals...

Preclinical and clinical activity of DZD1516, a full blood–brain barrier-penetrant, highly selective HER2 inhibitor

Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood–brain barrier (BBB) pene...

Non-progressive breast carcinomas detected at mammography screening: a population study

Some breast carcinomas detected at screening, especially ductal carcinoma in situ, may have limited potential for progression to symptomatic disease. To determine non-progression is a challenge, but if all scr...

MRI-based breast cancer radiogenomics using RNA profiling: association with subtypes in a single-center prospective study

There are few prospective studies on the correlations between MRI features and whole RNA-sequencing data in breast cancer according to molecular subtypes. The purpose of our study was to explore the associatio...

Effectiveness of palbociclib with aromatase inhibitors for the treatment of advanced breast cancer in an exposure retrospective cohort study: implications for clinical practice

New drugs for locally advanced or metastatic breast cancer have led to clinical benefits, aside with increasing costs to healthcare systems. The current financing model for health technology assessment (HTA) p...

Noninvasive imaging signatures of HER2 and HR using ADC in invasive breast cancer: repeatability, reproducibility, and association with pathological complete response to neoadjuvant chemotherapy

The immunohistochemical test (IHC) of HER2 and HR can provide prognostic information and treatment guidance for invasive breast cancer patients. We aimed to develop noninvasive image signatures IS HER2 and IS HR of...

Targeting the oncogenic transcription factor FOXM1 to improve outcomes in all subtypes of breast cancer

FOXM1 (Forkhead box M1) is an oncogenic transcription factor that is greatly upregulated in breast cancer and many other cancers where it promotes tumorigenesis, and cancer growth and progression. It is expres...

Transcriptionally regulated miR-26a-5p may act as BRCAness in Triple-Negative Breast Cancer

DNA damage and DNA damage repair (DDR) are important therapeutic targets for triple-negative breast cancer (TNBC), a subtype with limited chemotherapy efficiency and poor outcome. However, the role of microRNA...

RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling

RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM +ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM imp...

Meeting Abstracts from the British Society of Breast Radiology Annual Scientific Meeting 2022

This article is part of a Supplement: Volume 25 Supplement 1

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2 : the BRCA1 and BRCA2 Cohort Consortium

Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA...

BluePrint molecular subtypes predict response to neoadjuvant pertuzumab in HER2-positive breast cancer

The introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain which pati...

Correction to: National and subnational burden of female and male breast cancer and risk factors in Iran from 1990 to 2019: results from the Global Burden of Disease study 2019

The original article was published in Breast Cancer Research 2023 25 :47

Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness

Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of BRCA-like tum...

Estrogen receptor blockade and radiation therapy cooperate to enhance the response of immunologically cold ER+ breast cancer to immunotherapy

Most patients with estrogen receptor positive (ER+) breast cancer do not respond to immune checkpoint inhibition (ICI); the tumor microenvironment (TME) of these cancers is generally immunosuppressive and cont...

XENERA-1: a randomised double-blind Phase II trial of xentuzumab in combination with everolimus and exemestane versus everolimus and exemestane in patients with hormone receptor-positive/HER2-negative metastatic breast cancer and non-visceral disease

Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuz...

Influence of alcohol consumption and alcohol metabolism variants on breast cancer risk among Black women: results from the AMBER consortium

Moderate to heavy alcohol consumption is associated with an increased risk of breast cancer. The etiologic role of genetic variation in genes involved in ethanol metabolism has not been established, with littl...

Noninvasive prediction of axillary lymph node breast cancer metastasis using morphometric analysis of nodal tumor microvessels in a contrast-free ultrasound approach

Changes in microcirculation of axillary lymph nodes (ALNs) may indicate metastasis. Reliable noninvasive imaging technique to quantify such variations is lacking. We aim to develop and investigate a contrast-f...

Studying the association between longitudinal mammographic density measurements and breast cancer risk: a joint modelling approach

Researchers have suggested that longitudinal trajectories of mammographic breast density (MD) can be used to understand changes in breast cancer (BC) risk over a woman’s lifetime. Some have suggested, based on...

Infiltrating myeloid cell diversity determines oncological characteristics and clinical outcomes in breast cancer

Breast cancer presents as one of the top health threats to women around the world. Myeloid cells are the most abundant cells and the major immune coordinator in breast cancer tumor microenvironment (TME), targ...

Targeting CXCR4 abrogates resistance to trastuzumab by blocking cell cycle progression and synergizes with docetaxel in breast cancer treatment

Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not r...

Head-to-head comparison of perfluorobutane contrast-enhanced US and multiparametric MRI for breast cancer: a prospective, multicenter study

Multiparametric magnetic resonance imaging (MP-MRI) has high sensitivity for diagnosing breast cancers but cannot always be used as a routine diagnostic tool. The present study aimed to evaluate whether the di...

Progesterone from ovulatory menstrual cycles is an important cause of breast cancer

Many factors, including reproductive hormones, have been linked to a woman’s risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs...

Breast metastatic tumors in lung can be substituted by lung-derived malignant cells transformed by alternative splicing H19 lncRNA

Metastasis accounts for most cancer-associated deaths; yet, this complex process remains poorly understood, particularly the relationship between distant metastasis and primary site-derived cells. Here, we mod...

Molecular profiling of a real-world breast cancer cohort with genetically inferred ancestries reveals actionable tumor biology differences between European ancestry and African ancestry patient populations

Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of Afr...

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Breast Cancer Research

ISSN: 1465-542X

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Current State of Breast Cancer Diagnosis, Treatment, and Theranostics

Affiliations.

• 1 Ladue Horton Watkins High School, St. Louis, MO 63124, USA.
• 2 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
• PMID: 34069059
• PMCID: PMC8156889
• DOI: 10.3390/pharmaceutics13050723

Breast cancer is one of the leading causes of cancer-related morbidity and mortality in women worldwide. Early diagnosis and effective treatment of all types of cancers are crucial for a positive prognosis. Patients with small tumor sizes at the time of their diagnosis have a significantly higher survival rate and a significantly reduced probability of the cancer being fatal. Therefore, many novel technologies are being developed for early detection of primary tumors, as well as distant metastases and recurrent disease, for effective breast cancer management. Theranostics has emerged as a new paradigm for the simultaneous diagnosis, imaging, and treatment of cancers. It has the potential to provide timely and improved patient care via personalized therapy. In nanotheranostics, cell-specific targeting moieties, imaging agents, and therapeutic agents can be embedded within a single formulation for effective treatment. In this review, we will highlight the different diagnosis techniques and treatment strategies for breast cancer management and explore recent advances in breast cancer theranostics. Our main focus will be to summarize recent trends and technologies in breast cancer diagnosis and treatment as reported in recent research papers and patents and discuss future perspectives for effective breast cancer therapy.

Keywords: breast cancer; breast specific gamma imaging; imaging modalities; mammography; theranostics; triple-negative breast cancer.

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• v.13(11); 2017

Risk Factors and Preventions of Breast Cancer

Yi-sheng sun.

1 Key Lab of Vaccine against Hemorrhagic Fever with Renal Syndrome, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China;

2 Centre of Laboratory Medicine, Zhejiang Provincial People's Hospital.

Zhang-Nv Yang

Hang-jing lu, zhi-yong zhu, jianmin jiang, ping-ping yao, han-ping zhu.

Breast cancer is the second leading cause of cancer deaths among women. The development of breast cancer is a multi-step process involving multiple cell types, and its prevention remains challenging in the world. Early diagnosis of breast cancer is one of the best approaches to prevent this disease. In some developed countries, the 5-year relative survival rate of breast cancer patients is above 80% due to early prevention. In the recent decade, great progress has been made in the understanding of breast cancer as well as in the development of preventative methods. The pathogenesis and tumor drug-resistant mechanisms are revealed by discovering breast cancer stem cells, and many genes are found related to breast cancer. Currently, people have more drug options for the chemoprevention of breast cancer, while biological prevention has been recently developed to improve patients' quality of life. In this review, we will summarize key studies of pathogenesis, related genes, risk factors and preventative methods on breast cancer over the past years. These findings represent a small step in the long fight against breast cancer.

Introduction

Breast cancer is one of the most common cancers in women worldwide, accounting for approximately 570,000 deaths in 2015. Over 1.5 million women (25% of all women with cancer) are diagnosed with breast cancer every year throughout the world 1 , 2 . In America, it is estimated that 30% of all new cancer cases (252,710) among women are breast cancer in 2017 3 . Breast cancer is a metastatic cancer and can commonly transfer to distant organs such as the bone, liver, lung and brain, which mainly accounts for its incurability. Early diagnosis of the disease can lead to a good prognosis and a high survival rate. In North American, the 5-year relative survival rate of breast cancer patients is above 80% due to the timely detection of this disease 4 . Mammography is a widely used screening approach in the detecting of breast cancer and proved to help reduce the mortality effectively. Other screening methods, such as Magnetic Resonance Imaging (MRI), which is more sensitive than mammography, have also been implemented and studied during the last decade 5 . There're numerous risk factors such as sex, aging, estrogen, family history, gene mutations and unhealthy lifestyle, which can increase the possibility of developing breast cancer 6 . Most breast cancer occur in women and the number of cases is 100 times higher in women than that in men 3 . Although the incidence rate of breast cancer in America increases year after year, the mortality rate decreases due to the widespread early screenings and advanced medical therapies. Biological therapies have been developed in recent years and proved to be beneficial for breast cancer. Here, we will focus on studies of the pathogenesis, related genes, risk factors and preventions of breast cancer over the past years.

Pathogenesis

Breast tumors usually start from the ductal hyperproliferation, and then develop into benign tumors or even metastatic carcinomas after constantly stimulation by various carcinogenic factors. Tumor microenvironments such as the stromal influences or macrophages play vital roles in breast cancer initiation and progression. The mammary gland of rats could be induced to neoplasms when only the stroma was exposed to carcinogens, not the extracellular matrix or the epithelium 7 , 8 . Macrophages can generate a mutagenic inflammatory microenvironment, which can promote angiogenesis and enable cancer cells to escape immune rejection 9 , 10 . Different DNA methylation patterns have been observed between the normal and tumor-associated microenvironments, indicating that epigenetic modifications in the tumor microenvironment can promote the carcinogenesis 11 , 12 . Recently, a new subclass of malignant cells within tumors called the cancer stem cells (CSCs) are observed and associated with tumor initiation, escape and recurrence. This small population of cells, which may develop from stem cells or progenitor cells in normal tissues, have self-renewal abilities and are resistant to conventional therapies such as chemotherapy and radiotherapy 13 - 15 . Breast cancer stem cells (bCSCs) were first identified by Ai Hajj and even as few as 100 bCSCs could form new tumors in the immunocompromised mice 16 . bCSCs are more likely to originate from luminal epithelial progenitors rather than from basal stem cells 17 . Signaling pathways including Wnt, Notch, Hedgehog, p53, PI3K and HIF are involved in the self-renewal, proliferation and invasion of bCSCs 18 - 21 . However, more studies are needed to understand bCSCs and to develop novel strategies to directly eliminate the bCSCs.

There're two hypothetical theories for breast cancer initiation and progression: the cancer stem cell theory and the stochastic theory 11 , 22 . The cancer stem cell theory suggests that all tumor subtypes are derived from the same stem cells or transit-amplifying cells (progenitor cells). Acquired genetic and epigenetic mutations in stem cells or progenitor cells will lead to different tumor phenotypes (Figure ​ (Figure1A). 1 A). The stochastic theory is that each tumor subtype is initiated from a single cell type (stem cell, progenitor cell, or differentiated cell) (Figure ​ (Figure1B). 1 B). Random mutations can gradually accumulate in any breast cells, leading to their transformation into tumor cells when adequate mutations have accumulated. Although both theories are supported by plenty of data, neither can fully explain the origin of human breast cancer.

Two hypothetical theories of breast cancer initiation and progression. (A) All subtypes of tumor are derived from the same stem cells or progenitor cells. Different tumor phenotypes are then determined by subtype-specific transforming events. (B) Each tumor subtype is initiated from a single cell type (stem cell, progenitor cell, or differentiated cell). Random mutations can gradually accumulate in any breast cells, leading to their transformation into tumor cells when an adequate number of mutations have accumulated.

Genes related to breast cancer

Lots of genes have been identified in relation to breast cancer. Mutations and abnormal amplification of both oncogenes and anti-oncogenes play key roles in the processes of tumor initiation and progression.

Breast cancer associated gene 1 and 2 ( BRCA1 and BRCA2 ) are two famous anti-oncogenes for breast cancer risk. BRCA1 and BRCA2 are located on chromosome 17q21 and 13q12, respectively. They both encode tumor suppressor proteins. BRCA1 deficiency leads to the dysregulation of cell cycle checkpoint, abnormal centrosome duplication, genetic instability and eventually apoptosis 23 , 24 . BRCA1 expression is repressed by “pocket proteins” such as p130, p107 and the retinoblastoma protein in an E2F-dependent manner. The BRCA1 gene has been shown to form a loop between the promoter, introns, and terminator regions, which regulates the expression of this gene via interactions with its own promoter 25 , 26 . BRCA2 protein regulates recombinational repair in DNA double-strand breaks by interacting with RAD51 and DMC1 27 , 28 . BRCA2-associated breast cancers are more likely to be high-grade invasive ductal carcinomas, but with a luminal phenotype 29 . The risk of breast cancer could be increased greatly if an individual inherits deleterious mutations in either BRCA1 or BRCA2 genes. BRCA1/2 mutations are inherited in an autosomal dominant manner even though the second allele is normal. Totally, about 20-25% of hereditary breast cancers and 5-10% of all breast cancers are caused by BRCA1/2 mutations 30 , 31 . A meta-analysis by Chen showed that the breast cancer risk ratio in women older than 70 years carrying BRCA1 or BRCA2 mutations was 57% and 49%, respectively 32 .

Human epidermal growth factor receptor 2, also known as c-erbB-2 , is an important oncogene in breast cancer and located on the long arm of human chromosome 17 (17q12). The homologene in mice is Neu , which was first identified in 3-methylcholanthrene induced rat neuroblastoma cells 33 . The expression of HER2 gene is activated mainly through the gene amplification and re-arrangement. HER2 protein is an epidermal growth factor receptor (EGFR) of tyrosine kinase family and form heterodimers with other ligand-bound EGFR family members such as Her3 and Her4, thus to activate downstream signaling pathways 34 . Knockout of HER2 in mouse models disrupts normal mammary duct formation. Overexpression of HER2, which is detected in about 20% of primary breast cancers, increases the number of cancer stem cells by PTEN/Akt/mTORC1 signaling, and indicates poor clinical outcomes 35 , 36 .

Epidermal Growth Factor Receptor (EGFR)

EGFR , also known as c-erbB-1 or Her1 in humans, is located on the short arm of chromosome 7 (7p12). The EGFR protein is a cell surface glycoprotein of tyrosine kinase family and is activated by binding to EGF, TGF-α, amphiregulin, betacellulin and so on. The downstream signaling pathways of EGFR including PI3K, Ras-Raf-MAPK and JNK are triggered to promote cell proliferation, cell invasion, angiogenesis and to protect cells against apoptosis 37 , 38 . Overexpression of EGFR is found in more than 30% of cases of the inflammatory breast cancer (IBC), a very aggressive subtype of breast cancer. Patients with EGFR -positive IBC have a poorer prognosis than those with EGFR -negative tumors 39 , 40 . More than half of triple-negative breast cancer (TNBC) cases, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) expression and HER2 amplification, also have EGFR overexpression 41 . Therefore, targeting the EGFR pathway might be a promising therapy for these malignant tumors.

This gene is located on the long arm of chromosome 8 (8q24) and encodes for the Myc protein, a transcription factor containing the bHLH/LZ (basic Helix-Loop-Helix Leucine Zipper) domain. Genome-wide screening shows that 15% of all genes are regulated by the Myc protein mainly through binding on the E-box consensus (CACGTG) and recruiting histone acetyltransferases (HATs) or DNA methyltransferases 42 , 43 . Some of the Myc-regulated genes such as MTA1 , hTERT and PEG10 play vital roles in breast cancer initiation and progression. The overexpression of c-Myc is predominantly observed in the high-grade, invasive stage of breast carcinomas, while no c-Myc amplification is detected in the benign tissues 44 , 45 .

Other related genes

There're three members in the Ras gene family: H-ras, K-ras and N-ras , located on the chromosome of 11 (11p15), 12 (12p12) and 1 (1p22) respectively. The proteins encoded by these genes are extremely homologous, and they belong to the small guanosine triphosphate (GTP)-binding protein (G protein) superfamily 46 . Point mutations are commonly associated with the overexpression of these three human Ras genes, and most are missense mutations located at the coding domain for GTP binding. Though mutations of Ras proteins are infrequently in breast cancer (<5%), the abnormality of Ras signal transduction pathway are observed in both benign and malignant mammary tissues 47 . H-ras can cooperate with B lymphoma moloney murine leukaemia virus insertion region-1 (BMI1) to promote proliferation, invasion, and to inhibit apoptosis in breast cancer cells 48 . H-ras overexpression is detected in both primary and advanced breast cancer patients, indicating a poor prognosis 49 , 50 .

Risk factors

A schematic diagram of risk factors is depicted in a pyramid-style structure (Figure ​ (Figure2 2 ).

Schematic diagram of risk factors and preventions of breast cancer. Age, family history, reproductive factors, estrogen and life style are five important risk factors of breast cancer, represented in the pyramid chart. Screening (mammography and MRI), chemoprevention (with SERMs and AIs) and biological prevention (using Herceptin and pertuzumab) are currently being used to prevent breast cancer. PD1/PDL1 inhibitors are immunotherapy drugs and might be promising strategies in treating TNBC.

Besides sex, aging is one of the most important risk factors of breast cancer, because the incidence of breast cancer is highly related to the increasing age. In 2016, approximately 99.3% and 71.2% of all breast cancer-associated deaths in America were reported in women over the age of 40 and 60, respectively 3 . Therefore, it is necessary to have a mammography screening ahead of time in women aged 40 or older.

Family history

Nearly a quarter of all breast cancer cases are related to family history 65 . Women, whose mother or sister has a breast cancer, are prone to this disease. A cohort study of over 113,000 women in UK demonstrated that women with one first-degree relative with breast cancer have a 1.75-fold higher risk of developing this disease than women without any affected relatives. Moreover, the risk becomes 2.5-fold or higher in women with two or more first-degree relatives with breast cancer 65 . The inherited susceptibility to breast cancer is partially attributed to the mutations of breast cancer related genes such as BRCA1 and BRCA2 .

Reproductive factors

Reproductive factors such as early menarche, late menopause, late age at first pregnancy and low parity can increase the breast cancer risk. Each 1-year delay in menopause increases the risk of breast cancer by 3%. Each 1-year delay in menarche or each additional birth decreases the risk of breast cancer by 5% or 10%, respectively 66 - 68 . A recent Norwegian cohort study showed that a hazard ratio (HR) is 1.54 between late (≥35 years) and early (<20 years) age at first birth 69 . Reproductive factors are strongly associated with the ER status, with differences in the odds ratios (OR) between ER + and ER - breast cancer for parity (OR: 0.7 vs. 0.9 for ≥3 births vs. nulliparae) and age at the first birth (OR: 1.6 vs. 1.2 for age ≥30 vs. <25 years) 70 .

Both endogenous and exogenous estrogens are associated with the risk of breast cancer. The endogenous estrogen is usually produced by the ovary in premenopausal women and ovariectomy can reduce the risk of breast cancer 71 . The main sources of exogenous estrogen are the oral contraceptives and the hormone replacement therapy (HRT). The oral contraceptives have been widely used since 1960s and the formulations have been upgraded to reduce side-effects. However, the OR is still higher than 1.5 for African American women and Iranian populations 72 , 73 . Nevertheless, oral contraceptives do not increase the risk of breast cancer in women who stop to use them for more than 10 years 66 . HRT involves the administration of exogenous estrogen or other hormones for the menopausal or postmenopausal women. A number of studies have shown that the use of HRT can increase the breast cancer risk. The Million Women Study in UK reported a relative risk (RR) of 1.66 between current users of HRT and those who never used it 74 . A cohort study of 22,929 women in Asia demonstrated HRs of 1.48 and 1.95 after HRT use for 4 and 8 years, respectively 75 . However, the risk of breast cancer has been shown to significantly decrease after two years of stopping HRT 76 . The recurrence rate is also high among breast cancer survivors who take HRT, and the HR for a new breast tumor is 3.6 77 . Since the adverse effects of HRT were published in 2003 based on the Women's Health Initiative randomized controlled trial, the incidence rate of breast cancer in America has decreased by approximately 7% due to the reduction in the use of HRT 78 .

Modern lifestyles such as excessive alcohol consumption and too much dietary fat intake can increase the risk of breast cancer. Alcohol consumption can elevate the level of estrogen-related hormones in the blood and trigger the estrogen receptor pathways. A meta-analysis based on 53 epidemiological studies indicated that an intake of 35-44 grams of alcohol per day can increase the risk of breast cancer by 32%, with a 7.1% increase in the RR for each additional 10 grams of alcohol per day 79 , 80 . Modern western diet contains too much fat and excess intake of fat, especially the saturated fat, is associated with mortality (RR=1.3) and poor prognosis in breast cancer patients 81 . Although the relationship between smoking and breast cancer risk remains controversial, mutagens from cigarette smoke have been detected in the breast fluid from non-lactating women. The risk of breast cancer is also elevated in women who both smoke and drink (RR=1.54) 82 . Up to now, accumulating evidences demonstrate that smoking, especially at an early age, has a higher risk on breast cancer occurrence 83 - 86 .

Preventions

Thus far, great advances have been made in clinical and theoretical studies of breast cancer (Figure ​ (Figure2). 2 ). The current prevention methods including screening, chemoprevention and biological prevention are more direct and effective than those in the past (Figure ​ (Figure2). 2 ). The mortality of breast cancer has decreased. However, breast cancer is still the first leading cause of cancer death among females aged 20-59 years.

Not primary tumors but the tumor metastasis causes over 90% of cancer deaths 87 . However, if breast cancer is diagnosed as a primary tumor or at an early stage of metastasis, the breast tumor could be removed by surgery and the chemotherapy could work effectively. Early detection is the cornerstone of breast cancer prevention. Mammography is an effective screening method to use low energy X-rays to obtain high-resolution images of the breast. The entire testing process only lasts for 20 minutes and it does not require any contrast-enhancing agent. Since the first recommendation for breast cancer screening by Professor Forrest, over 70% of women (aged 50-74 years) in America have been undergone breast cancer screening via mammography every 2 years 88 . A meta-analysis of 11 randomized trials showed that women aged 50-70 years had a significant reduction in breast cancer mortality after screening with mammography (RR=0.81) 89 . However, the reduction in mortality rate was not significant in women aged 40-49 years 90 . These results indicate the importance of mammography screening programs. Although the reported percentage of overdiagnosis due to mammography varies across trials, overdiagnosis is undoubtedly a serious problem that cannot be ignored during breast cancer screening.

MRI is another widely used screening tool for breast cancer. It is more sensitive than mammography in high-risk women, especially in detecting the invasive ductal carcinoma 91 . Compared to mammography, MRI is not affected by the breast density and has advantages in detecting occult primary breast cancer, axillary nodal metastasis, residual tumors after neoadjuvant chemotherapy or other small tumors 92 . Advanced MRI scanners can measure tissues as small as 0.5 mm 3 . However, there's no identified benefit of MRI in patient outcomes such as in the rate of detection of ipsilateral breast tumor recurrence and contralateral breast cancer incidence. The specificity of MRI is much poorer than that of mammography, with detection rates ranging from 37% to 100% 93 . Women with a family history of breast cancer have an approximately 20-25% or higher lifetime risk of breast cancer as demonstrated by MRI screening 94 . Each coin has two sides, and we should balance both the goodness and weakness. Considering its sensitivity, MRI may be a useful choice in high risk groups when the mammography results are normal.

Chemoprevention

The classical definition of chemotherapy by Sporn is “the use of pharmacologic or natural agents that inhibit the development of invasive breast cancer either by blocking the DNA damage that initiates carcinogenesis, or by arresting or reversing the progression of premalignant cells in which such damage has already occurred.” 95 . Estrogen receptor is a major target for chemotherapy because more than 70% of breast cancers are ER-positive breast cancers. Selective estrogen receptor modulators (SERMs) and the aromatase inhibitors (AIs) are two major classes of anti-estrogen drugs. SERMs are compounds that act as either agonists or antagonists of estrogen receptors. One of the most famous SERMs is tamoxifen (TAM), which has been used to treat breast cancer for more than 30 years 96 . Regardless of the number, the scale, the related areas or the time lasting in the follow-up visit of TAM's research, this drug has no doubt the most abundant clinical data in SERMs. Meanwhile, TAM is used to treat all stages of breast cancer 97 . Many large-scale trials including the Breast Cancer Prevention Trial (NSABP-1), the Royal Marsden Prevention Trial, the Italian Prevention Trial and the International Breast Cancer Intervention Study (IBIS-I Trial) have shown that TAM could reduce the risk of both invasive and non-invasive breast cancer. Despite the differences in data collection and study design, all these trials have demonstrated greater than 30% reduction in ER-positive breast cancer after 5 years treatment with TAM. However, no significant reduction has been observed in ER-negative tumors 98 , 99 . Nevertheless, there're some side-effects of TAM therapy. The risk of endometrial cancer, stroke, pulmonary embolism, and deep-vein thrombosis is increased in TAM-treated patients, and the risk is especially high among women older than 50 100 . Therefore, TAM should be used individually by balancing between its toxicity and benefits.

Raloxifene, a second generation of SERMs with fewer side-effects than TAM, has been approved for the treatment of invasive breast cancer in postmenopausal women as well as osteoporosis and heart disease 101 . However, raloxifene shows no effect on ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). The Study of Tamoxifen and Raloxifene (STAR) trials showed that raloxifene was less effective than TAM 99 . Considering its less risk in endometrial cancers and thromboembolic complications, raloxifene is still a good therapeutic option for the invasive breast cancer. Several third generations of SERMs such as ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) have also been discovered, but only BZA has reached the stage of clinical use. BZA has demonstrated potent effects in pre-clinical studies, but its efficacy was limited in pivotal clinical trials 102 .

Recently, AIs are being used instead of TAM as the first line therapy in postmenopausal breast cancer patients. AIs reduce the plasma levels of estrogens by inhibiting aromatase, an enzyme that catalyzes the biosynthesis of estrogen from androgen 103 . There're two classes of AIs: steroidal inhibitors and non-steroidal inhibitors. Compared with exemestane, a steroidal inhibitor, non-steroidal inhibitors such as anastrozole and letrozole can bind to the enzyme's active site reversibly. However, these three third-generation AIs (exemestane, anastrozole and letrozole) have no significant differences in terms of efficacy in preventing breast cancer. Many trials such as the Italian Tamoxifen Anastrozole (ITA) trial, Intergroup Exemestane Study (IES), Austrian Breast and Colorectal Cancer Study Group (ABCSG-8), and the Breast International Group (BIG) 1-98 study have showed that in the adjuvant setting, AIs are more potent than TAM in reducing the incidence of breast cancer both as upfront monotherapy and after 2-3 years treatment with tamoxifen 104 - 110 . A 10-year ATAC trial study indicated fewer serious side-effects for anastrozole than for tamoxifen in postmenopausal women with early ER + breast cancer 111 . However, there're some limitations of AIs. Because AIs inhibit the biosynthesis of estrogen, they are typically used only in postmenopausal women. The main side-effect of AIs is that they can increase the risk of osteoporosis, which is a significant health threat for older women. Other side-effects, such as joint pain and stiffness, incidence of carpal tunnel syndrome or dysregulated lipid metabolism, have also been reported for AIs, but these side-effects have a lower impact on the quality of life of patients than endometrial cancer and thromboembolic complications associated with TAM treatment. Acquired resistance to AIs has been observed after prolonged treatment, which also occurs in the case of SERMs. Crosstalks between estrogen receptor pathway and several signaling pathways such as PI3K/Akt/mTOR and Ras/Raf/MEK/MAPK could lead cancer cells to be resistant to AIs 112 . The combination of AIs and inhibitors of the related signaling pathways may be a promising strategy for AI-resistant patients.

Biological prevention

Recently, biological prevention, mainly known as the monoclonal antibodies for the breast cancer, has been developed to improve the quality of life in breast cancer patients. One of the major targets of these monoclonal antibodies is HER2. About 20-30% of all breast cancer cases exhibit HER2 protein overexpression or HER2 gene amplification 36 . Trastuzumab (Herceptin), a recombinant humanized monoclonal antibody, is the first HER2-targeted drug to be approved by the FDA. It can directly interact with the C-terminal portion of domain IV in the extracellular part of HER2 113 , 114 . Up to now, the anti-tumor mechanism of trastuzumab has not been clearly elucidated. Some potential mechanisms may be that trastuzumab can suppress the growth and proliferation of cancer cells by recruiting ubiquitin to internalize and degrade HER2, by activating the immune system against cancer cells via a mechanism called antibody-dependent cell-mediated cytotoxicity (ADCC) or by inhibiting the MAPK and PI3K/Akt pathways 115 - 117 . Trastuzumab was initially used for treating metastatic breast cancer (MBC) and found to be efficacious as a single agent with an objective response rate (ORR) of 26%. In vitro experiments have shown that trastuzumab has a synergistic effect with other anti-tumor drugs such as nimotuzumab, carboplatin, 4-hydroxycyclophosphamide, docetaxel and vinorelbine 118 , 119 . The HERA and TRAIN trials demonstrated that chemotherapy combined with adjuvant trastuzumab for 1 year could improve the disease-free survival in patients with HER2 + breast cancer (HR=0.76) 120 , 121 . A randomized phase II trial executed by Marty also showed that trastuzumab plus docetaxel was more efficacious than docetaxel alone in treating HER2-positive MBC, with the ORR of 50% versus 32% 122 . However, side-effects such as congestive heart failure and left ventricular ejection fraction (LVEF) decline were found in trastuzumab-treated patients 123 .

Similar to trastuzumab, pertuzumab (Perjeta), another humanized monoclonal antibody, can bind to the extracellular portion of HER2 like trastuzumab. However, the binding domain is different 124 . Pertuzumab combined with trastuzumab and docetaxel has been approved for treating HER2-positive breast cancer. The pathologic complete response (pCR) rate, as well as invasive-disease-free survival rate, significantly increased in HER + tumors than those in HER - tumors (57.8% versus 22.0%) 125 , 126 . However, toxic side-effects like diarrhea and febrile neutropenia were common in pertuzumab-treated groups.

Recently, immunotherapy becomes a hot spot in cancer therapy, and it shows great potential in clinical use. Programmed cell death 1 (PD1) is a membrane protein expressed in various immune cells, including T cells, which can be engaged by its specific ligand to block the immune system. PD1 inhibitor drugs Nivolumab (Opdivo) and Pembrolizumab (Keytruda) were approved for the treatment of several solid tumors such as metastatic melanoma and non-small cell lung cancer. In the KEYNOTE-012 study, pembrolizumab was found to be effective in 27 TNBC patients with a clinical benefit rate of 20% 127 . Programmed cell death receptor ligand 1 (PDL1), a ligand of PD1, is detected in 20% of TNBC and in 50% of all breast cancers 128 . PDL1 inhibitor drug Atezolizumab (Tecentriq) exhibits a 19% of objective response rate in a phase Ⅰ study including 54 TNBC patients 129 . Though TNBC patients typically have poor clinical outcomes, anti-PD1/PDL1 drugs might be promising strategies for treating this subtype of breast cancer.

Conclusion and further directions

Breast cancer is the most frequently diagnosed cancer in women across 140 countries 1 . Approximately 1 in 8 women worldwide have a lifetime risk of developing breast cancer 130 . Breast cancer develops through a multistep process, and the pathogenesis of this disease has not yet been elucidated. In the last decade, the tumor microenvironment and breast CSCs have been identified as contributors to breast tumorigenesis. Breast cancer is also influenced by genetic and environmental factors. Targeted prevention strategies against these risk factors should be taken ahead of time.

Although the incidence rate of breast cancer is high in developed countries, the fact which we can't ignore is that almost half of the breast cancer cases and over half of deaths occur in developing countries. The 5-year relative survival rates of breast cancer varied widely in developed and developing countries. The rate is over 80% in North American and Japan, but below 40% in Africa countries like Algeria. Breast cancer is a preventable disease, and there are adequate medical resources available in developed countries, which can protect against this disease, such as annual mammography screening or the daily use of chemopreventative drugs. These may be attributable for the higher survival rate of breast cancer patients in developed countries than that in middle-income or low-income countries. Considering the financial burden of developing countries, the clinical breast examination is an effective way to diagnose breast cancer in the early stage. Moreover, if women are educated about breast cancer, breast self-examination may be a simple, economical and motivated method to prevent this disease. People know their own bodies more clearly than any doctors. However, most of the women in developing countries don't realize the importance of breast cancer prevention. Therefore, in these countries, more attention should be focused on breast health promotion ahead of clinical treatment.

Nowadays, with the reduction in the cost of DNA sequencing, individual genome sequencing may be affordable by middle-class populations, and this could be a new method in preventing breast cancer. If a woman have a family history of breast cancer, it is wise to do a screen especially on hereditary cancer susceptibility genes such as BRCA1 or BRCA2 . The risk of breast cancer could then be evaluated based on the screening results and prevention advice could be offered personally. Individual genome sequencing may be a mainstream in the future for prevention of breast cancer as well as other hereditary disease. Additionally, risk factors should be taken more seriously either in normal or high-risk women. Environmental factors such as the exogenous estrogen intake, alcohol abuse and excess dietary fat consumption could be avoided to minimize breast cancer risk. Though some risk facts such as aging and reproductive factors are inevitable, measures should be taken ahead of time to reduce the risk. In the modern world, many people spend countless hours sitting at tables. People are more engaged in mental work rather than in physical work. However, physically active women have a 25% lower risk of breast cancer on average than women who are less active 131 . Regular physical exercise may be a convenient and inexpensive way to prevent breast cancer in women from both developed and developing countries.

Although traditional film mammography has limitations in detecting dense breasts, digital mammography can overcome this deficiency. It can capture images directly through an X-ray-sensitive detector and the digital data are analyzed in the computer. The Digital Mammographic Imaging Screening Trial (DMIST) showed that digital mammography had a better diagnostic performance than film mammography in pre- and perimenopausal women with dense breasts who were younger than 50 years of age. With advancements in digital technology, high-resolution digital mammography may replace film mammography in the future 132 . What's more, both mammography and MRI screening for a large population of women are expensive and only countries with good health insurance systems can offer these services. Direct breast ultrasonography, an adjuvant technique method to mammography and MRI, is less expensive and could be used widely in low- and middle-income countries. The ultrasonography is much more accurate if the operator is skilled and experienced.

Although great progress has been made in breast cancer prevention in the last decade, there is still a lack of effective therapies against TNBC. TNBC tends to have a higher relapse risk and is more aggressive than other subtypes, resulting in a poor 5-year survival rate 133 . Due to the absence of ER/PR expression and HER2 amplification, drugs targeted against these three receptors are useless in TNBC. In the last decade, several potential biomarkers in TNBC such as EGFR, androgen receptor (AR), PARP and mTOR, and microRNA-based biomarkers, such as miR-374b-5p and miR-629-3p have been identified and explored for targeted therapies 134 - 136 . The EGFR-inhibitor cetuximab combined with cisplatin increased the progression-free survival from 1.5 to 3.7 months, and the overall survival from 9.4 to 12.9 months in a phase Ⅱ clinical trial 137 . Expressions of AR is observed in 30% of TNBC patients, and the AR inhibitor bicalutaminde showed a clinical benefit rate of 19% in ER/PR negative breast cancer patients in a phase Ⅱ study 138 , 139 . PARP-inhibitor iniparib plus chemotherapy were also tested and showed promising results in phase Ⅰ and Ⅱ clinical trials. However, the phase III clinical trial failed with the lack of improvement in progression-free survival and overall survival 140 . Targeting the PI3K/AKT/mTOR pathway was thought to be an effective strategy to treat TNBC recently, and the mTOR inhibitor everolimus combined with doxorubicin and bevacizumab increased the objective response rate but not the clinical benefit rate 141 . Although many biomarker-based trials have been performed in TNBC, none has been successful finally. One of the main reasons for this failure could be the heterogeneity of TNBC. More work is needed to elucidate tumor heterogeneity, and the discovery of a robust biomarker regardless of tumor heterogeneity may be a breakthrough in TNBC treatment. Immunotherapy agents such as anti-PD1/PDL1 drugs will also shed light on treating TNBC.

In summary, breast cancer is preventable. Reducing risk factors and taking chemoprevention are two main measures to prevent breast cancer. However, there's a long way to go in creating public breast cancer awareness. Only 4.1% of high-risk women are willing to take chemoprevention drugs 142 . The fear of adverse effects and lack of understanding of breast cancer might be attributable for this unwillingness. Although, the Gail model or the IBIS model is widely used for determining the risk of breast cancer based on a woman's age, family history, race and reproductive factors, we still lack a reliable strategy to exactly evaluate the risk ratio of breast cancer. With improvements in sequencing technology, individual genome sequencing may be a powerful method to evaluate the risk of breast cancer. Better medicines with less adverse effects and a favorable risk-benefit ratio need to be developed in the future.

Additional genes associated with breast cancer

Notes: SNP-Single Nucleotide Polymorphisms; HR-Hazard ratio

Acknowledgments

We would like to thank Dr. Yan-Ling Wu for her advice on this paper. This work is supported by Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ15C040001 and LY18H190003, Social Development Project of Public Welfare Technology Research in Zhejiang Province (LGF18H100002), and Zhejiang Provincial Foundation for Scientific Research in Medicine and Health (2015RCB009).