Risk Factor For Development Of Breast Cancer Research Articles

Melatonin, circadian rhythms and breast cancer

Breast cancer (BC) is the leading cause of morbidity and mortality of malignant neoplasms in women worldwide. In spite of a large number of studies devoted to the etiopathogenesis of this group of malignant tumors, many questions concerning specific mechanisms of their origin and development are still unresearched. Based on numerous studies in recent years, in addition to traditional risk factors (such as hereditary factors, hormonal disorders, environmental factors, etc.), foreign and Russian authors have identified a new risk factor for BC development - the sphere of molecular disorders affecting circadian rhythms and circadian genes, as well as metabolic and regulatory intracellular pathways regulated by them. It has been shown that the balance between oncogenes and suppressor genes and processes such as neoangiogenesis, metastasis and antitumor immune response depend on the functioning of the circadian rhythm system. One of the key metabolites in the circadian rhythm regulation system is melatonin, which physiological effects extend not only to the central nervous system, but also to peripheral tissue cells. The study of the relationship between circadian rhythm disturbances, melatonin secretion and malignant tumors is one of the important tasks of modern oncology. In the present review the following aspects of this problem are considered in detail: relationships between circadian rhythms, melatonin and BC; molecular mechanisms of melatonin antitumor action in BC; therapeutic potential of melatonin in prevention and treatment of malignant breast tumors as a direct antitumor agent, a component of accompanying treatment, and as a radiosensitizer and radioprotector for radiotherapy. The purpose of this review is to investigate the problem of the relationship between the circadian rhythm system, melatonin and molecular mechanisms of development and progression of breast malignancies, as well as the therapeutic potential of melatonin in their prevention and treatment. The review is based on the study of relevant and reliable scientific articles, reviews, meta-analyses, systematic reviews, and clinical trials published in Scopus, PubMed, Web of Science and in peer-reviewed Russian journals mainly during the last 5 years.

Gut and Breast Microbiota as Endocrine Regulators of Hormone Receptor-positive Breast Cancer Risk and Therapy Response.

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor-positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential antitumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine-targeting therapies may influence or be influenced by the microbiota and how that may affect carcinogenesis initiation and tumor recurrence.

A Comprehensive Review on Multifaceted Mechanisms Involved in the Development of Breast Cancer Following Adverse Childhood Experiences (ACEs).

Background and aim of the work. Adverse Childhood Experiences (ACEs) may give rise to harmful effects on health throughout life. Epigenetic changes explain how preexisting risk factors may contribute to produce altered biological responses and cancer risk. The main aim of the review is to summarize studies examining the means in which Adverse Childhood Experiences (ACEs) can modulate individual vulnerability to breast cancer (BC) development through multifaceted mechanisms. Methods. Studies selection, data extraction, and assessments agreed to PRISMA criteria. We included original research with clinical samples following BC interventions, investigating potential mechanisms linking ACEs and BC in adults. Results. From the 3321 papers found, nine articles involving 2931 participants were selected. All studies included ACEs retrospective assessments and psychological measures, and seven of them considered biomarkers. Individuals exposed to greater ACEs were at increased BC risk compared with individuals with no ACEs. Associations were found between child abuse and/or neglect, depression, perceived stress, fatigue, and plasma levels of cytokines interleukin (IL-6), C-reactive protein (CRP), soluble tumor necrosis factor receptor type II (sTNF-RII), interleukin IL-1 receptor antagonist (IL-1ra), and psycho-physiological adjustments that may lead to BC. Conclusions. Exposure to multiple ACEs appears a risk factor for BC development in adulthood. Although the clinical relevance of findings such as this is ambiguous, the review added evidence for a link between the presence of childhood adversity and BC occurrence, pointing to psychological, hormonal, and immunological dysregulations.

Breast Cancer Screening and Diagnostic Advancements

The best tool to detect breast cancer (BC) is `screening`. Earlier screening improves prognosis and better treatment outcomes. Screening is basically looking for different signs before the appearance of actual symptoms. The process of screening specifically used for BC is known as mammography.
 Mammography is an explicit kind of imaging system that uses X-Rays (low dose) to ascertain cancer in breasts. This diagnostic procedure is in practice since the past 30 years but in the past 15 years, there is an improved set of techniques being introduced resulting in better results. Recently, three major diagnostic procedures for breast cancer which are in vogue include digital mammography, computer-aided testing and tomosynthesis. Out of these 3 diagnostic tools, tomosynthesis, furthermore branded as three-dimensional (3-D) mammography and digital tomosynthesis, is the supreme and innovative system of breast imaging where numerous pictures of the breast from diverse angles are taken and remodeled ("synthesized") resulting in formation of a three-dimensional group of images. That is why, 3-D imaging technique is alike computed tomography imaging system in which a sequences of thin "slices" are gathered to formulate a 3-D reformation of the body.
 Even though the strength of radiation for few tomosynthesis systems is higher to some extent as compared to power of the dosage used in typical mammography, but as long as it is in the predefined radiation limit approved by FDA it`s not harmful. Some of the systems have doses comparable to conventional mammography. Some previous studies on large populations have proved that breast screening with tomosynthesis have resulted in enhanced the rate of detection of breast cancer detection rates and it has also decreased the chances of recalls, especially at occasions where females are called back for screening for added testing because of a possibly uncharacteristic finding.
 Tomosynthesis has an edge on other diagnostic procedures as it may help in prior recognition of cancerous lesions that may be not be revealed on a conventional mammogram, it also eradicates the need for small number of preventable biopsies or supplementary testing and increases the probability of detection of several breast tumors. It also provides stronger imagining of irregularities within condensed breast tissue and greater precision in pinpointing the location, size and shape of breast anomalies.
 Women should at least get a standard mammogram once a year beginning at age 40. The major risk factors for BC development are old age, inactivity, reproductive history, genetic mutations, family history of ovarian or BC, being overweight or obese after menopause, history of administration of hormones. Also, if someone, have had radiation treatment to the chest in the past, it’s highly recommended that such women should have annual mammograms at a younger age (often beginning around age 30).

Targeting FoxP3 gene to check out the impairment of tolerance in breast cancer patients

ObjectiveFoxP3 gene is a potential gene in the development of Breast Cancer (BC). Mutated expression of this gene shows some correspondence with tumorigenic activity for this reason it is important to understand. The principal goal of this study was the mutational analysis of the FoxP3 gene in BC patients. This research also provides the basic functions and genetic details on the FoxP3 gene in the Lahore population, especially how the FoxP3 gene acts as a risk factor in BC development. The study design was Cross-sectional. MethodsGenomic DNA was extracted from peripheral blood samples of BC patients. Amplified products were electrophoretically separated and target PCR products were sequenced with a Sanger sequencing analyzer. The main purpose is to determine the order of nucleotides in the FoxP3 gene. Further mutations were analyzed by the chromatograms using Chromas, NCBI nucleotide BLAST X, and the Mutation Surveyor. After that, different protein-coding sequences were studied. ResultsThe substitution occurs at location 324 where T is replaced by A and in another sample G is replaced by A at position 328 while in the third sample InDel mutation was observed at position 28. ConclusionIn the current study, intronic variants typically in the FoxP3 gene exon 2 region were confirmed by computational analysis using a gene database. We investigated nucleotide mutations in FoxP3 in patients with malignant breast tumors, along with their association with various characteristics such as marriage status, age of menopause, miscarriage and lactation history, and family history. A better understanding of the FoxP3 gene in the etiology and progression of breast cancer can reveal many explorable problems, including the clinical implications of the FoxP3 gene. However, these intronic variations are of massive importance and demonstrated that this enhancer can establish a physical interaction with a promoter site binding nuclear factor-κB components necessary for T cell regulation.

Human Papillomavirus in Breast Carcinogenesis: A Passenger, a Cofactor, or a Causal Agent?

Simple SummaryBreast cancer (BC) is the most frequent tumor in women worldwide. A minority of BC patients have a family history of the disease, suggesting the importance of environmental and lifestyle factors. Human papillomavirus (HPV) infection has been detected in a subset of tumors, suggesting a potential role in BC. In this review, we summarized relevant information in respect to this topic and we propose a model of HPV-mediated breast carcinogenesis. Evidence suggests that breast tissue is accessible to HPV, which may be a causal agent of BC in a subset of cases.Breast cancer (BC) is the most commonly diagnosed malignancy in women worldwide as well as the leading cause of cancer-related death in this gender. Studies have identified that human papillomavirus (HPV) is a potential risk factor for BC development. While vaccines that protect against oncogenic HPVs infection have been commercially available, global disparities persist due to their high cost. Interestingly, numerous authors have detected an increased high risk (HR)-HPV infection in BC specimens when compared with non-tumor tissues. Therefore, it was suggested that HR-HPV infection could play a role in breast carcinogenesis in a subset of cases. Additional epidemiological and experimental evidence is still needed regarding the role of HR-HPV infection in the development and progression of BC.

151P Impact of germline BRCA (gBRCA) mutation (m) status on clinical characteristics and patterns of care among women with early breast cancer (eBC): An analysis of the observational prospective CANTO cohort

Genetic mutations on breast cancer (BC) susceptibility genes such as BRCA 1 or 2, are well known risk factors for BC development. 5-10% of BC are associated with a gBRCAm, which can impact tumor characteristics and management of the associated BC. Using the French prospective ongoing CANTO cohort (NCT01993498) we conducted a retrospective analysis focusing on clinical characteristics and patterns of care of eBC by gBRCA status.

Relationship Between Proliferative Breast Lesions and Breast Cancer Risk Factors.

The prognosis of breast cancer (BC) is determined directly based on the stage of disease at the time of diagnosis. Proliferative breast lesions (PBLs) are an important risk factor for BC development. The risk of developing BC varies according to the presence of extent of proliferation in the breast lesions. We aimed to investigate the effect of BC risk factors on the PBLs in this study. Patients who visited the surgical clinic of the university during the past 6 years who presented with PBLs with or without atypia by fine/core needle aspiration biopsy were included in this study. The relationship between PBLs and BC risk factors such as the age, mass size, Body Mass index (BMI), smoking, sports activity, BC family history, the use of hormone replacement therapy, number of pregnancies, and the duration of breastfeeding were compared. A total of 74 (96.1%) of all patients were women and three were men. The median age of the patients was 38 (range: 19-74) years; the cut-off value of age was 35.5 years. The mean age of patients with PBL-with atypia (PBL-WA) was higher (p=0.005) in the malignant group based on the final pathology and radiological imaging features (for both, p<0.001). The mean size of the mass was large at 2.53±1.33 (1-6) cm; and the cut-off value of the tumor size was 2.5 cm. The mean size was greater in the PBL-WA patients (p=0.171) in the malignant group based on the final pathology and radiological characteristic (respectively, p=0.004 and p=0.016). The mean BMI was 26.8±4.4 kg/m2 (18.8-35.1) and the cut-off value was 25.4 kg/m2. BMI was greater in the PBL-WA group and in the malignant group based on the final pathology (respectively, p=0.002 and p=0.001). Smoking was positive in 66.2% (n=51) of the patients, and it was high in the PBL-WA patients (p=0.001). The percentage of patients with no sports activity was 63.6% (n=49), while it was 20.8% (n=16) for those with once a week sports activity and 15.6% (n=12) for those with twice a week activity. There was family history of BC in 16.9% (n=13) of all patients. The number of positive cases of family history of BC was greater in the malignant group (p=0.001). Hormone replacement therapy was recorded in 11.7% (n=9) of the patients. The mean numbers of pregnancies (2.1±2.4) and breastfeeding duration (32.5±37.4 months) were low in the benign groups due to the relatively lower average age of the patients. Based on our analysis, age is an extremely important aspect for assessing PBLs. The age of the patient was statistically significantly greater in the patients with malignant lesions in all groups. The factors lesion size, BMI, smoking habit, and BC family history were also more frequent in the malignant groups. The rate of sports activity was lower in the malignant groups. Thus, it is necessary to evaluate patients individually when evaluating PBLs. It is recommended to evaluate PBLs together with BC risk factors for the better understanding.

Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment.

Simple SummaryIn this review we discuss the recent knowledge about the role of breast and gut microbiome in the pathogenesis of breast cancer. We examine the proposed mechanisms of interaction between breast tumors and the microbiome. We focus on the role of the microbiome in: (i) the development and maintenance of estrogen metabolism through bacterial beta-glucuronidase enzymes (ii) the regulation of the host´s immune system and tumor immunity by Treg lymphocyte proliferation through bacterial metabolites such as butyrate and propionate (SCFAs), (iii) the induction of chronic inflammation, (iv) the response and/or resistance to treatments and (v) the epigenetic reprogramming. Moreover, we also discuss that diet, probiotics and prebiotics could exert important anticarcinogenic effects in breast cancer that could indicate their employment as adjuvants in standard-of-care breast cancer treatments. Overall, these findings could give new insights for building up novel strategies for breast cancer prevention and treatment.In breast cancer (BC) the employment of sequencing technologies for metagenomic analyses has allowed not only the description of the overall metagenomic landscape but also the specific microbial changes and their functional implications. Most of the available data suggest that BC is related to bacterial dysbiosis in both the gut microenvironment and breast tissue. It is hypothesized that changes in the composition and functions of several breast and gut bacterial taxa may contribute to BC development and progression through several pathways. One of the most prominent roles of gut microbiota is the regulation of steroid-hormone metabolism, such as estrogens, a component playing an important role as risk factor in BC development, especially in postmenopausal women. On the other hand, breast and gut resident microbiota are the link in the reciprocal interactions between cancer cells and their local environment, since microbiota are capable of modulating mucosal and systemic immune responses. Several in vivo and in vitro studies show remarkable evidence that diet, probiotics and prebiotics could exert important anticarcinogenic effects in BC. Moreover, gut microbiota have an important role in the metabolism of chemotherapeutic drugs and in the activity of immunogenic chemotherapies since they are a potential dominant mediator in the response to cancer therapy. Then, the microbiome impact in BC is multi-factorial, and the gut and breast tissue bacteria population could be important in regulating the local immune system, in tumor formation and progression and in therapy response and/or resistance.

Abstract 184: Three-dimensional density model promotes invasive characteristics in normal mammary epithelial cells

Abstract Background: Breast cancer (BC) is the most diagnosed cancer and the fourth leading cause of cancer related mortality among women. One of the highest risk factors for developing BC is dense breast tissue. Mammographic density (MD) is defined by the amount of stromal and epithelial tissues present in the breast. Approximately, 50% of women in the US have high MD and are 4-6 times more likely to develop BC in their lifetime. The stromal microenvironment is characterized by extracellular matrix (ECM) reorganization and stiffness. One of the most abundant molecules in ECM is collagen type I (Col1). High Col1 expression is seen in women with high MD and is also correlated with cell proliferation, survival, and invasion. Unfortunately, the underlying cellular and molecular mechanisms for the association between MD and BC are poorly understood. Therefore, understanding the molecular pathways involved in the unique transformation of normal mammary epithelial cells (nMECs) to cancer cells in a dense microenvironment is an important step in finding diagnostic tools and therapeutic targets for prevention and treatment of BC. My hypothesis is that 3-dimensional (3D) collagen-dense matrix promotes an invasive phenotype and activates oncogenic cell signaling pathways in nMECs, and hTERT-HME1 cell line, contributing to their transformation. Methods: I conducted an in vitro study using hTERT cells cultured in 3D COL1-dense gels todetermine the phenotypical changes and cellular signaling alterations caused by high collagen density. Results: I have observed that hTERT cells in high 3D COL1-dense gels form invasive phenotypes with protrusive structure compared to cells in low density gels. My previous data shows that, hTERT cells cultured in 2D-COL1 coated plates will express mesenchymal markers and over-express ERK1/2 and PI3K pathways which promote cancer cell proliferation and tumor cell survival. My plan is to further analyze the oncogenic cell signaling pathways that drive the transformation of hTERT cells into invasive cells, using my 3D COL1-dense gels. These pro-oncogenic pathways include, MAPK pathway, PI3 Kinase pathway, the activation of Epithelial to Mesenchymal Transition (EMT) markers as well as the expression level of tumor-associated MUC1 (tMUC1) . Unlike MUC1, tMUC1 is hypo-glycosylated and is over expressed in more than 90% of invasive breast carcinomas. I plan to investigate the pathway of association between inflammation caused by dense tissue, MUC1 signaling and cell transformation that could drive carcinogenesis. Conclusion: A collagen-stiff mammary microenvironment can induce carcinogenic phenotypes and cell signaling behavior in nMECs, which highlights the possible first steps in the transformation of nMECs into cancer cells. Given that high MD is one of the major risk factors for BC development, it is critical to decipher the molecular mechanisms associated with the high risk. Citation Format: Shayan Nazari, Pinku Mukherjee. Three-dimensional density model promotes invasive characteristics in normal mammary epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 184.

Vitamin D status, receptor gene BsmI (A/G) polymorphism and breast cancer in a group of Egyptian females

BackgroundVitamin D is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. The present study aimed to investigate vitamin D status and the genetic polymorphism BsmI (A/G) of vitamin D receptor (VDR) among a group of Egyptian female patients with breast cancer. MethodsThe current study included 60 female patients diagnosed as breast cancer (BC) attending Mansoura Oncology Center, Mansoura University, and 60 age-matched healthy control females. Serum 25(OH) vitamin D level was measured using Enzyme-linked immunosorbent assay (ELISA) kit. A polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method and fragment analysis were performed to determine the VDR BsmI (A/G) polymorphism. Results25(OH) vitamin D levels were significantly lower in the patients with BC (22.1±10.9ng/ml) compared to controls (41.2±11.22ng/ml) (p⩽0.001). Vitamin D deficiency- insufficiency was reported in 76.7% of BC patients and 20% of the controls (P⩽0.001, OR=13.1, 95%CI=5.5−31.4). Bb genotype was statistically higher in the BC patients than in the healthy controls (P⩽0.001). 81.2% of BC patients were of Bb genotype, 10.9% of BB genotype and 4.3% of bb genotype, while in controls, 33.3% for each genotype. No statistically significant difference in allele frequency was observed between the two studied groups. Carriers of Bb genotype had 4.6times increased risk of developing breast cancer (95% confidence interval of 2.0–10.3) when compared to other genotypes. ConclusionA significant association exists between vitamin D deficiency and the risk of breast cancer. B allele or Bb genotype of VDR may be a susceptibility risk factor for BC development.

Does hepatitis B virus infection cause breast cancer?

Lifestyle and family history are two of the most important risk factors for breast cancer (BC). However, these risk factors cannot explain the differences in the incidence and early BC onset among Chinese females compared to their western counterparts. We propose in this hypothesis the potential mechanism of indirect oncogenesis of hepatitis B virus (HBV) in causing BC through its persistence as occult infection and continuous replication with long term subtle liver damage. Estrogen is mainly deactivated in the liver and long term necro-inflammatory damage to liver may result in persistent high level of estrogen, which is a dominant risk factor for BC. HBV may also directly affect the breast cells through its cis and trans effects of HBx which may act as oncoprotein. Given the recognised aetiologic association between oestrogen and breast cancer risk, there is biological plausibility that dietary soy and vegetable intake which is rich in the Chinese diet may have anti-carcinogenic effect on the breast. The seemingly conflicting phenomenon of early age onset and lower BC incidence in China might be due to wide imbalance in the amount of exposure to carcinogenic factor (e.g., HBV infection) for decades and the carcinoprotective exposure levels (e.g., isoflavonoids and flavonoids intake). For example, the increase in carcinoprotective levels would lead to lower incidence of breast cancer and vice versa. Although the focus of this personal view is on HBV, this by no means negates the roles of other known risk factors in breast-cancer development. Characterisation of the role of HBV in BC could potentially benefit Chinese females by decreasing incidence and increasing overall survival.

Abstract P3-05-12: Circulating oxysterol metabolites as potential new surrogate markers for hormonotherapy in patients with hormone receptor-positive breast cancer? A pilot study

Abstract Background: Clinicians need new predictive biomarkers of response to hormonal therapy in patients (pts) with hormone receptor-positive (HR+) breast cancer (BC). Current treatments used the selective estrogen receptor modulator tamoxifen (Tam) or aromatase inhibitors (AI). Several data from the literature and our preclinical results indicate that cholesterol metabolism pathway is involved in BC oncogenesis and sensitivity/resistance to Tam. Our team has established that Tam modulates cholesterol oxydative metabolism and modulate oxysterol (OS) levels in vitro and in vivo on BC cell lines. Tam is a potent inhibitor of the cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of cholesterol epoxides (CEs) and the inhibition formation of cholesterol triol (CT). Importantly, we found that CEs mediated the cytotoxicity of Tam in BC. Therefore, an increase in CEs, and no increase in CT could be markers of the efficacy of Tam reflecting its inhibition of ChEH in pts. On the other hand 27-hydroxycholesterol (27HC), another OS, is an estrogen receptor ligand with tumor promoter properties in BC. The 27HC level could constitute a new risk factor for BC development that has to be measured. The impact of AI on cholesterol metabolism is totally unknown, it is thus important to study its impact on OS levels in pts. Methods: We have conducted a monocentric, prospective, clinical trial in pts who must received Tam or AI in adjuvant or metastatic setting for a HR+ BC. The primary end point was the feasibility of detection of circulating OS (CEs, CT and 27HC) in the serum of patients before the first administration of hormonal therapy and at 1 month. Key secondary end points were to measure variations in the concentration of OS according to patients and treatments. 12 different OS including CEs, CT and 27HC were quantified by GC/MS. Results : bCE relative concentration significantly increased in the entire population (p=0.0109) while no increase in CT was measured under HT treatment establishing that Tam inhibited ChEH in pts. It should be noted that an important inter-individual variability in pts was observed according the OS species considered. AI stimulated the accumulation of βCE (p=0.0022) suggesting that they modulate CEs metabolism. We found that AI were not direct inhibitors of ChEH in BC cells suggesting that they modulate CEs level through a different mechanism than Tam. Importantly, we found that letrozol, but not exemestane or Tam, increased the blood level in 27-HC. This suggests that letrozol increased a factor of BC risk since 27HC is a tumor promoter which may be involved in BC recurrence. Conclusion: This pilot study provides the first evidence that circulating OS could be measured in the blood of pts with BC. The clinical utility of OS as biomarkers of sensibility/resistance to hormone therapy needs further clinical investigations. Based on the present study the CE/27HC ratio should be more specifically investigated. The mechanisms involved in the modulation of OS by AI deserve further studies. Citation Format: Florence Dalenc, Luggi Iuliano, Thomas Filleron, Maud Voisin, Henri Roché, Sandrine Silvente-Poirot, Marc Poirot. Circulating oxysterol metabolites as potential new surrogate markers for hormonotherapy in patients with hormone receptor-positive breast cancer? A pilot study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-12.

Does iron have a role in breast cancer?

Oestrogen and family history are two of the most important risk factors for breast cancer. However, these risk factors cannot explain the differences in the incidence and recurrence of breast cancer between premenopausal and postmenopausal women. In this paper I propose that, in premenopausal women, an iron deficiency caused by menstruation stabilises hypoxia inducible factor-1alpha, which increases the formation of vascular endothelial growth factor. This mechanism results in premenopausal women being more susceptible to angiogenesis and, consequently, leads to a high recurrence of breast cancer. Conversely, increased concentrations of iron in postmenopausal women, as a result of menstrual cessation, contribute to a high incidence of breast cancer via oxidative-stress pathways. Although the focus of this Personal View is on iron, this by no means negates the roles of other known risk factors in breast-cancer development. Characterisation of the role of iron in breast cancer could potentially benefit patients by decreasing recurrence and incidence and increasing overall survival.

Benign breast disease as a breast cancer risk in Japanese women.

A hospital‐based retrospective cohort study of benign breast disease (BBD) as a risk factor of future breast cancer (BC) development was conducted. Four hundred and twenty‐eight patients with biopsied BBD were followed‐up for a median period of 8 years, together with age‐matched women with normal breasts (normal control) and BC patients (cancer control), at the ratio of 1:2:2. Twenty‐one breast cancers developed, 7 in the cases, 4 in the normal controls, and 10 in the BC controls, showing the relative risk (RR) with 95% confidence intervals (CD to be 3.5 (1.03–11.9) in the cases with respect to the normal controls. The RR of the cases is not lower than that of contralateral breast cancer incidence. There were no significant differences in the risks of cancers in other organs among the groups. Pathological examination revealed that only atypical hyperplasia increased the RR of BC, as compared with the normal control breast group, or with non‐proliferative disease. These results suggest that in a low‐risk country, Japan, BBD is a definite risk factor for BC development as in high‐risk countries.