Etiology Of Breast Cancer Research Articles

Serum perfluorooctane sulfonate and perfluorooctanoate and risk of postmenopausal breast cancer according to hormone receptor status: An analysis in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Per- and polyfluoroalkyl substances (PFAS) are highly persistent endocrine-disrupting chemicals that may contribute to breast cancer development; however, epidemiologic evidence is limited. We investigated associations between prediagnostic serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and postmenopausal breast cancer risk, overall and by hormone receptor status, in a nested case-control study of 621 cases and 621 matched controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. PFOS and PFOA levels were determined based on serum metabolomic profiling performed using ultraperformance liquid chromatography-tandem mass spectrometry. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each PFAS and breast cancer risk, overall, by estrogen receptor (ER) or progesterone receptor (PR) status, and by joint ER/PR status. We found little evidence of association between PFOS or PFOA and breast cancer risk overall. However, in subtype-specific analyses, we observed statistically significant increased risks of ER+, PR+, and ER+/PR+ tumors for the third vs lowest quartile of serum PFOS (ORs [95% CIs]=1.59 [1.01-2.50], 2.34 [1.29-4.23], and 2.19 [1.21-3.98], respectively) and elevated but nonstatistically significant ORs for the fourth quartile. Conversely, for PFOA, modest positive associations with ER-, PR-, ER+/PR-, and ER-/PR- tumors were generally seen in the upper quartiles. Our findings contribute evidence supporting positive associations between serum PFOS and hormone receptor-positive tumors, and possibly between PFOA and receptor-negative tumors. Future prospective studies incorporating tumor hormone receptor status are needed to better understand the role of PFAS in breast cancer etiology.

Abstract P2-06-03: Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort

Abstract Background: Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods: This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n= 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results: The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions: Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food. Citation Format: Alice Bellicha, Gaëlle Wendeu-Foyet, Xavier Coumoul, Meriem Koual, Fabrice Pierre, Françoise Guéraud, Laurent Zelek, Charlotte Debras, Bernard Srour, Laury Sellem, Emmanuelle Kesse-Guyot, Chantal Julia, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-03.

Abstract P6-05-10: An international survey on invasive lobular breast cancer (ILC) reveals gaps in knowledge and top priority research areas

Abstract Background: There is growing awareness of the unique etiology, biology, clinical presentation and progression of Invasive lobular breast cancer (ILC), but additional research is needed to assure translation of findings into management and treatment guidelines. We performed a survey to: 1) analyze the landscape of the current understanding of ILC, and 2) identify consensus research questions on ILC. Methods: The IRB-approved survey was developed with input from representatives of three major stakeholder groups - breast cancer clinicians/researchers, laboratory-based researchers, and advocates/patients. We fielded the survey from March to May 2022 using targeted email and via social media. Results: 1,774 participants answered at least one question and 1,310 finished the survey. Participants are from 66 countries from all continents (except Antarctica). Respondents self-identified as clinicians (mostly medical oncologists and surgeons) (N=413), researchers (N=376), and breast cancer patients (1,121), with some belonging to more than one category. 26% of the patients who participated in the survey belong to advocate groups. Only 46% of clinicians reported being confident in describing the differences between ILC and no special type (NST) (invasive ductal) breast cancer. Knowledge of histology was seen as important (73%), affecting their treatment decisions (51%), and refined treatment guidelines would be valuable for patients with ILC in the future (76%). 85% of clinicians have never powered a clinical trial to allow subset analysis for histological subtypes, but the majority would consider it. 88% would participate in a consortium to conduct clinical trials on ILC. The top two most important research questions were: 1) determining mechanisms of endocrine resistance, and, 2) identifying novel therapeutic targets, repurposing existing drugs and progressing them to clinical trials. Of the researchers, 48% reported being confident in describing differences between ILC and NST. They reported that ILCs are inadequately presented in large genomic data sets (52%), and that ILC models are insufficient (42%). Only 13% of respondents have inadequate access to tissue or blood from patients with ILC. The top two most important research questions identified by the laboratory researchers overlapped with those identified by the clinicians, i.e. understanding of endocrine resistance and identifying novel drugs that can be tested in clinical trials. The majority of patients (52%) thought that their health care providers did not explain unique features of ILC, and that in general communication was limited. When asked about top research question, they chose: 1) Improvement of ILC screening/early detection, and, 2) Identifying new and specific imaging tools for ILC. When comparing top priority topics across six research domains, there was a high degree of consistency, especially among clinicians and researcher, but less so when compared with the breast cancer patients (Table 1). Conclusion: In summary, we have gathered timely and representative information from an international community of clinicians, researchers, and patients/advocates that we expect will lay the foundation for a community-informed collaborative research agenda, with the goal of improving the management and personalizing treatment for patients with ILC. Table 1. Ratings by all three stakeholder groups of the most critical and impactful ILC research topics. Top box scores between stakeholder groups were compared using chi-square analysis. Citation Format: Steffi Oesterreich, Leigh Pate, ADRIAN V. LEE, Rachel C. Jankowitz, Patrick Derksen, Rita Mukhtar, Otto Metzger, Matthew J. Sikora, Christopher Li, Christos Sotiriou, Gary Ulaner, Jorge Reis-Filho, Nancy E Davidson, Karen Van Baelen, Laurie Hutcheson, Siobhan Freeney, Flora Migyanka, Claire Turner, Todd Bear, Christine Desmedt. An international survey on invasive lobular breast cancer (ILC) reveals gaps in knowledge and top priority research areas [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-10.

MiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.

Inference on the Genetic Architecture of Breast Cancer Risk.

What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors? The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ. Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii). First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants. This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477.

A prospective case–cohort analysis of plasma metabolites and breast cancer risk

BackgroundBreast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with breast cancer risk.MethodsUntargeted metabolomic analysis was done on prediagnostic plasma samples from a case–cohort study of 1695 incident breast cancer cases and a 1983 women subcohort drawn from Cancer Prevention Study 3. The associations of 868 named metabolites (per one standard deviation increase) with breast cancer were determined using Prentice-weighted Cox proportional hazards regression modeling.ResultsA total of 11 metabolites were associated with breast cancer at false discovery rate (FDR) < 0.05 with the majority having inverse association [ranging from RR = 0.85 (95% CI 0.80–0.92) to RR = 0.88 (95% CI 0.82–0.94)] and one having a positive association [RR = 1.14 (95% CI 1.06–1.23)]. An additional 50 metabolites were associated at FDR < 0.20 with inverse associations ranging from RR = 0.88 (95% CI 0.81–0.94) to RR = 0.91 (95% CI 0.85–0.98) and positive associations ranging from RR = 1.13 (95% CI 1.05–1.22) to RR = 1.11 (95% CI 1.02–1.20). Several of these associations validated the findings of previous metabolomic studies. These included findings that several progestogen and androgen steroids were associated with increased risk of breast cancer in postmenopausal women and four phospholipids, and the amino acids glutamine and asparagine were associated with decreased risk of this cancer in pre- and postmenopausal women. Several novel associations were also identified, including a positive association for syringol sulfate, a biomarker for smoked meat, and 3-methylcatechol sulfate and 3-hydroxypyridine glucuronide, which are metabolites of xenobiotics used for the production of pesticides and other products.ConclusionsOur study validated previous metabolite findings and identified novel metabolites associated with breast cancer risk, demonstrating the utility of large metabolomic studies to provide new leads for understanding breast cancer etiology. Our novel findings suggest that consumption of smoked meats and exposure to catechol and pyridine should be investigated as potential risk factors for breast cancer.

Abstract A070: Association between socioeconomic and clinical factors on timely access to care among young Black women with breast cancer

Abstract Background: Young-onset breast cancer is associated with higher mortality due to multiple factors including tumor biology and delayed presentation. Young women with breast cancer with longer treatment delays have decreased survival time, with the impact on survival being more prominent in Black women. The factors contributing to the racial survival disparity are complex and are likely an interplay between tumor biology, genomics, patterns of care and socioeconomic factors. This study looked at socioeconomic and clinical factors that may affect timely access to care for breast cancer in young Black women, and thus impact survival. Methods: Data from the Black Women Etiology and Survival of Triple-negative Breast Cancers (BEST) Study, a population-based cohort of Black women diagnosed with breast cancer ≤ 50 years old between 2009 and 2015 from the Florida and Tennessee State Cancer Registries was used. The time to treatment (in days) was used as the exposure variable and defined as the time from breast cancer diagnosis to the date of first treatment. The primary outcome was determined by distant or local recurrence or death. Pearson chi-square test was conducted to assess the association between clinical and socioeconomic factors with time to treatment. The socioeconomic variables studied were insurance, income and education. Clinical factors evaluated were the stage of breast cancer at diagnosis, hormone subtype, neoadjuvant chemotherapy and type of surgery. Survival analysis and Cox proportional hazard model were performed to analyze the 10-year overall survival and recurrence rate while adjusting for income, breast cancer stage and hormone subtype. Results: There was a statistically significant association between time to treatment and hormone receptor subtype (p=0.04). More than 60% of women with triple-negative breast cancer (TNBC), and 57% of women with HER2+ breast cancer received treatment within a month of their breast cancer diagnosis. There was also a significant association between the time to treatment and type of surgery received (p=0.03). 64% of patients who had lumpectomies received treatment in ≤30 days, compared to 54% of patients who had a mastectomy. Survival analysis showed the highest mortality in patients with time to treatment &amp;gt;90 days, followed by patients who received treatment in ≤30 days. The study did not find a statistically significant association between insurance, income, or education on the timeliness of treatment for breast cancer. Conclusion: In our study of young Black women, delayed breast cancer treatment resulted in lower survival. While those with TNBC and HER2+ disease were more likely to receive treatment ≤30 days, i.e. neoadjuvant chemotherapy to assess response to chemotherapy and the amount of residual disease at the time of the surgery, the enrichment for aggressive disease is likely the reason for the low survival observed in this group. Timely access to treatment for breast cancer impacts survival and strategies to decrease treatment delays are crucial to reducing breast cancer mortality. Citation Format: Kikelola Oyeleye, Rebecca Lee, Sonya Reid, Tuya Pal, Anne Weidner, Lindsay Venton. Association between socioeconomic and clinical factors on timely access to care among young Black women with breast cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A070.

Abstract A072: Genetic ancestry is related to potential sources of breast cancer health disparities among Colombian women

Abstract Introduction: Socioeconomic disadvantages can contribute to breast cancer health disparities among populations. However, it has been shown that other factors related to the etiology of breast cancer and the biology of the tumor, might also act as determinants of health disparities, as they can impact the patients’ treatment. To date, the relationship between these factors with genetic ancestry in a highly admixed population from Latin-America, has not yet been explored. Based on this, we aimed to assess contributing factors to breast cancer health disparities according to genetic ancestry in Colombian patients from a national cancer reference center. Methods: We revised clinical-pathological and socioeconomic data from breast cancer patients diagnosed at the National Cancer Institute (NCI) of Colombia and classified variables into the following groups: etiology-related factors (e.g., age of diagnosis), tumor-biology factors (e.g., tumor size), and socioeconomic factors (e.g., health insurance), each of which reflects potential sources of racial/ethnic disparities of breast cancer. We also considered variables related to treatment administration (e.g., neoadjuvant therapy) as an indicator of disease management. We applied a Kruskal–Wallis test to assess differences in genetic ancestry fractions according to each of the variables distribution. Results: A total of 308 Colombian breast cancer patients were included. Etiology-related factors analysis showed higher European ancestry fraction in patients diagnosed at older ages (&amp;gt;50 years: 50% vs. ≤50 years: 46%, p=0.017), and with smaller tumors (&amp;lt;20mm: 52% vs. ≥20mm: 48%, p=0.038). Higher Indigenous American (IA) ancestry was observed in patients with HER2-positive tumors compared to HER2-negative cases (44% vs. 40%. p=0.011). Additionally, patients with higher IA ancestry were more frequently treated with neoadjuvant therapy (NAT) (43% vs. no-NAT: 40%, p=0.050). Moreover, socioeconomic variables showed that patients that benefit from the government public health insurance, known in Colombia as subsidized regime, and those who are covered under their relative’s health insurance, known as beneficiaries, have a higher IA ancestry (43% and 43%, respectively, vs. 37%, p=0.016), compared to patients that do afford their own health insurance (contributory regime in Colombia); conversely, these patients presented a higher European ancestry (55% vs. subsidized: 47% and beneficiaries: 49%, p=0.011). Conclusions: Our results indicate that genetic ancestry is related to several potential sources of breast cancer health disparities that cover from tumor-biology factors like tumor size and HER2 expression to socioeconomic determinants like health insurance affiliation regime. Consequently, it is possible that genetic ancestry may partially reflect some differences in the disease management and in healthcare attention given to breast cancer patients in Colombia. Citation Format: Silvia J. Serrano-Gómez, Laura Rey-Vargas, Lina Bejarano, Juan Carlos Mejía-Henao, Maria Carolina Sanabria-Salas. Genetic ancestry is related to potential sources of breast cancer health disparities among Colombian women [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A072.

Advancements and Challenges in Breast Cancer: A Comprehensive Review

Introduction: Breast cancer is a global health concern, accounting for significant morbidity and mortality among women. The fragile ill prepared healthcare systems in low- &amp; middle-income countries need to address these challenges find solutions with their limited resources. Objectives: Through a critical examination of the literature, this article aims to contribute to a better understanding of breast cancer and to stimulate further research in this field. Methods &amp; Analysis: This review article provides an in-depth analysis of the current state of breast cancer research, focusing on advancements in diagnosis, treatment, and prevention, as well as the challenges and future directions. Conclusion: Emerging technologies, such as AI, 3D bioprinting, and nanotechnology, hold promise for addressing the challenges like management of metastatic disease, global disparities in outcomes, and the need for a better understanding of breast cancer etiology and revolutionizing breast cancer care.

A complex systems model of breast cancer etiology: The Paradigm II Model

A complex systems model of breast cancer etiology: The Paradigm II Model

Crosstalk between Methylation and ncRNAs in Breast Cancer: Therapeutic and Diagnostic Implications

Breast cancer, as a highly heterogeneous malignant tumor, is one of the primary causes of death among females worldwide. The etiology of breast cancer involves aberrant epigenetic mechanisms and abnormal expression of certain non-coding RNA (ncRNAs). DNA methylation, N6-methyladenosine(m6A), and histone methylation are widely explored epigenetic regulation types in breast cancer. ncRNAs are a group of unique RNA transcripts, mainly including microRNA (miRNAs), long non-coding RNA (lncRNAs), circular RNA (circRNAs), small interfering RNA (siRNAs), piwi-interacting RNA (piRNAs), etc. Different types of methylation and ncRNAs mutually regulate and interact to form intricate networks to mediate precisely breast cancer genesis. In this review, we elaborate on the crosstalk between major methylation modifications and ncRNAs and discuss the role of their interaction in promoting breast cancer oncogenesis. This review can provide novel insights into establishing a new diagnostic marker system on methylation patterns of ncRNAs and therapeutic perspectives of combining ncRNA oligonucleotides and phytochemical drugs for breast cancer therapy.

The Importance of Clinical Data &amp; Prevalence of Breast Tumors in South Punjab, Pakistan

Background: In Western countries, middle-aged women are more vulnerable to breast cancer. Globally, almost a million new cases were identified in 1998. One in 12 women in England and Wales will get the disease at some point.1 Even 5,000 years after it was first reported, the etiology of breast cancer is still unclear, and effective preventative measures are even further off. Aim: To characterize the varied ways in which breast cancer has presented itself among patients at Bahawal Victoria Hospital in Bahawalpur. Methods: This investigation employed a descriptive case series research design. This research was conducted at Bahawal Victoria Hospital's Surgery Department in Bahawalpur (Pakistan). From March 13th, 2020 through March 12th, 2021, the study was conducted (12 months). With their assent, 100 women with definite cases of breast cancer were enrolled in the study. Results: Cancer of the breast most commonly affected women between the ages of 31 and 50 (59%). Seventy-six patients arrived from the outlying rural areas of Bahawalpur and the neighboring districts. Only 18 patients had completed high school after 10 years and 5 patients were discovered to be college graduates. The single rate was 12%, with 12 patients. Eighty-one percent of patients reported having a breast lump. 56% of breast cancers involve the left breast, while 43% involve the right. One patient alone had breast cancer that had spread to both of her breasts. Illness duration varied from 1 month to 5 years. Stage III was the most prevalent presentation, with 46 instances, and Stage IV was the least common, with 16 patients. Practical implication Community based effective awareness and prompt screening programme will improve better outcomes in breast cancer management. Conclusion: Breast cancer is very common cancer in the females, and most commonly it presented as a lump in the breast, because of some social aspects, lack of awareness, poverty, no proper screening programs and above all the fear of diagnosis, females try to hide this problem and often it presented at late and more advance stage. Keywords: Breast, Nipple, Cancer, Lump, Surgery, Tumor

The Importance of Clinical Data &amp; Prevalence of Breast Tumors in South Punjab, Pakistan

Background: In Western countries, middle-aged women are more vulnerable to breast cancer. Globally, almost a million new cases were identified in 1998. One in 12 women in England and Wales will get the disease at some point.1 Even 5,000 years after it was first reported, the etiology of breast cancer is still unclear, and effective preventative measures are even further off. Aim: To characterize the varied ways in which breast cancer has presented itself among patients at Bahawal Victoria Hospital in Bahawalpur. Methods: This investigation employed a descriptive case series research design. This research was conducted at Bahawal Victoria Hospital's Surgery Department in Bahawalpur (Pakistan). From March 13th, 2020 through March 12th, 2021, the study was conducted (12 months). With their assent, 100 women with definite cases of breast cancer were enrolled in the study. Results: Cancer of the breast most commonly affected women between the ages of 31 and 50 (59%). Seventy-six patients arrived from the outlying rural areas of Bahawalpur and the neighboring districts. Only 18 patients had completed high school after 10 years and 5 patients were discovered to be college graduates. The single rate was 12%, with 12 patients. Eighty-one percent of patients reported having a breast lump. 56% of breast cancers involve the left breast, while 43% involve the right. One patient alone had breast cancer that had spread to both of her breasts. Illness duration varied from 1 month to 5 years. Stage III was the most prevalent presentation, with 46 instances, and Stage IV was the least common, with 16 patients. The histological hallmark most frequently attested by examination of slides was infiltrating ductal carcinoma, and this was the case in 87% of the cases. Conclusion: Breast cancer is very common cancer in the females, and most commonly it presented as a lump in the breast, because of some social aspects, lack of awareness, poverty, no proper screening programs and above all the fear of diagnosis, females try to hide this problem and often it presented at late and more advance stage. Keywords: Breast, Nipple, Cancer, Lump, Surgery, Tumor

Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study

BackgroundOnly a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer.MethodsWe conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from the UKB study (n = 194,174) and summary-level genetic outcome associations from the Breast Cancer Association Consortium (n = 228,951). Our exposures included all 34 biochemical biomarkers in the UKB, and our outcomes were overall, oestrogen-positive, and oestrogen-negative breast cancer. We performed inverse-variance weighted MR, weighted median MR, MR-Egger, and MR-PRESSO for 30 biomarkers for which we found multiple instrumental variables. We additionally performed multivariable MR to adjust for known risk factors, bidirectional MR to investigate reverse causation, and MR Bayesian model averaging to rank the significant biomarkers by their genetic evidence.ResultsIncreased genetic liability to overall breast cancer was robustly associated with the following biomarkers by decreasing importance: testosterone (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.04–1.21), high-density lipoprotein (HDL) cholesterol (OR: 1.08, 95% CI: 1.04–1.13), insulin-like growth factor 1 (OR: 1.08, 95% CI: 1.02–1.13), and alkaline phosphatase (ALP) (OR: 0.93, 95% CI: 0.89–0.98).ConclusionsOur findings support a likely causal role of genetically predicted levels of testosterone, HDL cholesterol, and IGF-1, as well as a novel potential role of ALP in breast cancer aetiology. Further studies are needed to understand full disease pathways that may inform breast cancer prevention.

Sp4 Regulates PTTG1IP Gene Transcription and Expression.

Pituitary tumor-transforming gene 1 protein (PTTG)-interacting protein, also known as PTTG-binding factor (PBF), is encoded by a proto-oncogene PTTG1IP. PBF has been identified through its interaction with PTTG. Similar to PTTG, PBF has been implicated in the etiology of several tumors, including pituitary, thyroid, and breast cancer. PBF can induce the translocation of PTTG into the nucleus, and then lead to tumorigenesis. Studies have shown that PBF plays a vital and complex role in increasing tumor development. However, the transcriptional regulation of PTTG1IP gene remains undefined. In this study, we have cloned a 467-bp fragment of the 5' flanking region of the human PTTG1IP gene and identified the region (-212 to +7 bp) necessary for PTTG1IP gene promoter activity by luciferase assay. Electrophoretic mobility shift assay revealed PTTG1IP gene promoter containing Sp4 response elements. Overexpression of Sp4 increased PTTG1IP gene transcription and expression in HeLa cells. Our study demonstrates that Sp4 regulates PTTG1IP gene transcription and expression.

Emerging potential of ubiquitin-specific proteases and ubiquitin-specific proteases inhibitors in breast cancer treatment.

Breast cancer is the most frequently diagnosed cancer in women, accounting for 30% of new diagnosing female cancers. Emerging evidence suggests that ubiquitin and ubiquitination played a role in a number of breast cancer etiology and progression processes. As the primary deubiquitinases in the family, ubiquitin-specific peptidases (USPs) are thought to represent potential therapeutic targets. The role of ubiquitin and ubiquitination in breast cancer, as well as the classification and involvement of USPs are discussed in this review, such as USP1, USP4, USP7, USP9X, USP14, USP18, USP20, USP22, USP25, USP37, and USP39. The reported USPs inhibitors investigated in breast cancer were also summarized, along with the signaling pathways involved in the investigation and its study phase. Despite no USP inhibitor has yet been approved for clinical use, the biological efficacy indicated their potential in breast cancer treatment. With the improvements in phenotypic discovery, we will know more about USPs and USPs inhibitors, developing more potent and selective clinical candidates for breast cancer.

Reproductive risk factors associated with breast cancer in young women by molecular subtype

BackgroundFew studies have examined detailed features of pregnancy and the postpartum period as potential risk factors for early onset breast cancer (BC) by molecular subtype. These data may have value for improving risk assessment and prevention. MethodsWe surveyed parous enrollees in the prospective Mayo Clinic Breast Disease Registry (MCBDR) who had been diagnosed with BC at age <55 years between 2015 and 2020. Summary statistics were used to describe survey responses and reproductive risk factors by BC subtype (defined by estrogen/progesterone receptors and human epidermal growth factor receptor expression, nurse-abstracted from the medical record). Associations were assessed with Kruskal-Wallis and Chi-Square tests, followed by age-adjusted linear and logistic regression models. We compared results from this parous cohort to those from a separate cohort of nulliparous MCBDR participants with BC diagnosed at age <55 years. ResultsIn 436 parous respondents with subtype data abstracted, we identified a higher frequency of BRCA1 mutation, earlier age at diagnosis, and lower BI in patients with triple negative BC. Comparing parous to nulliparous young women with breast cancer, the proportion with TNBC was larger in the latter (12.2% vs. 15.1%, p = 0.03). ConclusionsEarly age at diagnosis and deleterious BRCA1 mutation were more frequent among TNBC patients. In addition, parous young women with TNBC had a lower BI than those with other BC subtypes, a hypothesis-generating finding that supports the need for additional research on the cycle of pregnancy-lactation-postpartum involution and BC etiology.

Glucocorticoid induced loss of oestrogen receptor alpha gene methylation and restoration of sensitivity to fulvestrant in triple negative breast cancer

The response to psychological stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a “fight or flight response” and aid survival, whereas chronic long-term stress with the persistent release of stress hormones such as cortisol has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long-term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. A panel of triple negative breast cancer cell lines were treated with the glucocorticoid, cortisol which resulted in epigenetic alteration characterised by loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment.

Identification of a Risk Predictive Signature Based on Genes Associated with Tumor Size and Lymph Node Involvement in Breast Cancer.

Background: Breast cancer is a heterogeneous disease. Small tumors with extensive lymph node involvement (STEL) in breast cancer often reflect a biologically aggressive phenotype and poor prognosis. The aim of this study was to identify key genes associated with STEL and investigate their prognostic values in breast cancer. Methods: RNA sequence data from breast cancer specimens were acquired from The Cancer Genome Atlas (TCGA) database for differential analysis. Weighted gene correlation network analyses (WGCNA) were performed to identify coexpressed gene modules associated with tumor size and lymph node metastases. Gene set enrichment analysis (GSEA) was employed to investigate the biological functions of the identified genes. A combination of LASSO and Cox regression analyses was conducted to establish a risk predictive signature, and time-dependent receiver operating characteristic (tdROC) and Kaplan-Meier analyses were used to evaluate its prediction precision. Quantitative RT-PCR was employed to validate the expression levels of the key genes from the signature set. Results: A total of 2777 genes from three coexpressed gene modules were identified by WGCNA, and 880 differentially expressed genes were identified by transcriptome analyses. The 63 overlapping genes identified by both methods were considered STEL-associated genes, and a 9-gene risk-predictive signature was established based on them, with AUCs at 3, 5, and 7 years reaching 0.810, 0.811, and 0.753, respectively. Conclusion: This study demonstrated the transcriptomic profile of STEL breast cancer and successfully established a risk predictive signature with satisfactory accuracy. These findings may provide insights in to the genetic etiology of breast cancer.

Environmental and chemical risk factors for breast cancer

In Nigeria, breast cancer (BC) is currently the leading cause of cancer mortality, accounting for approximately 23% of all cancer diagnoses and 18% of all cancer deaths. Although the fundamental etiology of BC is still unknown, a number of risk factors, including age, lifestyle, menarche, menopause, and environmental exposures, among others, have been linked to the disease. There is mounting evidence that hazardous compounds that are part of our everyday environment are important risk variables. Exposure to these BC-predisposing chemicals happens through the items we use, the food we eat, the air we breathe, and the water we drink. Mostly, these are endocrine disrupting chemicals (EDCs) capable of mimicking hormones such as estrogen and progesterone with links to BC initiation and progression. EDCs, which include bisphenol A, dichlorodiphenyltrichloroethane, and polychlorinated biphenyls, among others, can be found in everyday items including plastic and metal containers, cosmetics, detergents, and insecticides. In addition, exposure to polycyclic aromatic hydrocarbons (PAHs), which are formed during the burning of organic materials and fuel, is another significant risk factor for BC. While BC initiation and pathogenesis are multifaceted with links to various contributing risk factors, a deeper understanding of the environmental and chemical conundrum will aid mitigating and prevention initiatives in Nigeria and elsewhere.