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This review links tumor initiation to a spectrum of risk determinants, covering non-modifiable factors (genetics, demographics, family history, mammographic density, reproductive milestones) and modifiable influences (hormone exposure, obesity, diet, physical inactivity). 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It also discusses reproductive history’s dual role.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does reproductive history influence breast cancer risk over time?",{"text":118,"@type":114},"The review describes a dual role: reproductive history can provide long-term protection while temporarily increasing breast cancer risk shortly after pregnancy.",{"name":120,"@type":111,"acceptedAnswer":121},"Which chemoprevention strategies are described as current options, and why are they limited?",{"text":122,"@type":114},"Current chemoprevention strategies primarily use selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene. 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Understanding Susceptibility to Breast Cancer: From Risk Factors to Prevention Strategies. Int. J. Mol. Sci. 2025, 26, 2993. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms26072993](10.3390/ijms26072993)  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Institute of Molecular and Cellular Biology of Cancer (IBMCC-CIC), CSIC-University of Salamanca,  \n37007 Salamanca, Spain; [rober.corchado@usal.es](rober.corchado@usal.es) (R.C.-C.); [jperezlosada@usal.es](jperezlosada@usal.es) (J.P.-L.)  \n2 Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain  \n* Correspondence: nataliagarciasancha@usal.es; Tel.: +34-923-29-48-20  \nAbstract: Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones, as well as modifiable risk factors like exogenous hormone exposure, obesity, diet, and physical inactivity. Importantly, reproductive history plays a dual role, providing long-term protection while temporarily increasing breast cancer risk shortly after pregnancy. Current chemoprevention strategies primarily depend on selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, which have demonstrated efficacy in reducing the incidence of estrogen receptor-positive breast cancer but remain underutilized due to adverse effects. Emerging approaches such as aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies show promise for expanding preventive options. Understanding the interactions between risk factors, hormonal influences, and tumorigenesis is critical for optimizing breast cancer prevention and advancing safer, more targeted chemopreventive interventions  \nKeywords: breast cancer; chemoprevention; risk factors; pregnancy; estrogens; tamoxifen; selective estrogen receptor modulators (SERMs)  \n1. Introduction  \nBreast cancer is the most frequently diagnosed cancer and the leading cause of cancerrelated mortality in women worldwide. In 2022, over 2.3 million new cases were reported, accounting for 11.6% of all cancer diagnoses, with incidence rates expected to surpass 3 million annually by 2040 [1,2] . While advances in early detection and treatment have improved survival, prevention remains a major challenge. The rising incidence of breast cancer is driven by demographic shifts, reproductive trends, and lifestyle changes, including increasing life expectancy, delayed childbearing, and the adoption of Westernized habits such as reduced physical activity and higher obesity rates [3–5] .  \nUnderstanding breast cancer risk factors is crucial for developing effective prevention strategies. These risk factors include genetic predisposition, reproductive history, lifestyle behaviors, and hormonal influences, all of which shape an individual’s susceptibility to the disease [6,7](Figure 1) . This review summarizes key risk factors for breast cancer ","cbCaia0LuudhGJg7","https://ap.wps.com/l/cbCaia0LuudhGJg7","pdf",1425038,32,"English","# Introduction\n## Breast Cancer Risk Factors\n### Non-Modifiable Breast Cancer Risk Factors\n### Germline Mutations and Single Nucleotide Polymorphisms","[{\"question\":\"What key risk factor categories does the review cover for breast cancer?\",\"answer\":\"The review covers non-modifiable risk factors (genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones) and modifiable risk factors (exogenous hormone exposure, obesity, diet, and physical inactivity). It also discusses reproductive history’s dual role.\"},{\"question\":\"How does reproductive history influence breast cancer risk over time?\",\"answer\":\"The review describes a dual role: reproductive history can provide long-term protection while temporarily increasing breast cancer risk shortly after pregnancy.\"},{\"question\":\"Which chemoprevention strategies are described as current options, and why are they limited?\",\"answer\":\"Current chemoprevention strategies primarily use selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene. They reduce incidence of estrogen receptor-positive breast cancer but remain underutilized because of adverse effects.\"},{\"question\":\"What emerging approaches are mentioned for expanding breast cancer prevention?\",\"answer\":\"The review highlights emerging approaches including aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies as promising options for broader preventive use.\"}]","Understanding Susceptibility to Breast Cancer: From Risk Factors to Prevention Strategies - Review | PDF",1790176590,81]