Unavoidable Factors (Non-Modifiable)
These intrinsic characteristics are inherent and cannot be altered, playing a significant role in an individual’s susceptibility to breast cancer.
Gender: Being a Woman is the Primary Risk
Women are considerably more prone to developing breast cancer than men, primarily due to hormonal differences and more extensive mammary tissue (1). This disparity is rooted in enhanced hormonal stimulation in females, which significantly influences breast tissue proliferation and differentiation (2).
Age:
As people get older, the chances of getting breast cancer go up. This is because genetic mutations build up and protective cellular mechanisms get weaker over time (3). This age-dependent increase is also affected by longer exposure to endogenous hormones and environmental factors that cause cellular damage and cancerous changes (4).
Family History:
A family history of breast cancer, particularly among first-degree relatives, substantially elevates an individual’s risk, underscoring the hereditary component of the disease (5). This familial predisposition often indicates shared genetic susceptibilities or common environmental exposures within a lineage (6). Moreover, shared genetic factors such as mutations in BRCA1 and BRCA2 genes significantly increase breast cancer risk (7).
Inherited Gene Mutations: BRCA and Beyond
Other genetic mutations, such as PALB2, CHEK2, and ATM, are also linked to a higher risk of breast cancer. This shows that there are more inherited genetic predispositions than just BRCA1 and BRCA2 (8). An individual’s lifetime risk can be determined by these mutations, which can cause abnormal cell growth, mostly in the milk ducts and lobules. Genetic changes, such as mutations in the ESR1 gene, are very common in breast cancers that are positive for estrogen receptors (ER+). These changes affect the activity of ER-alpha and help cancer cells grow and become resistant to drugs (1).
The genetic background or family history contributes to about 20–25% of all cases of breast cancer. Many loci, not just BRCA1 and BRCA2, make people more likely to get it (9). These genetic predispositions can interact with environmental factors, further altering an individual’s lifetime risk of developing the disease. It has been shown that the gene has a small role in the development of breast cancer. BRCA-1 is thought to be responsible for 5–10% of breast cancer that is passed down from one generation to the next (10).
Personal Health History: Previous Cancer and Benign Conditions
A previous diagnosis of breast cancer or specific benign breast conditions, including atypical hyperplasia, markedly elevates the risk of developing subsequent breast cancers (11) (12). This heightened risk arises from residual malignant cells, inherent genetic predispositions, or ongoing exposure to risk factors that instigated the primary cancer (13). Furthermore, prior radiation therapy, especially to the chest, head, or neck, significantly increases the risk of developing breast cancer later in life (1). On the other hand, people with certain gene mutations, such as those in TP53, often have a shorter half-life of wild-type p53 proteins, which makes it harder for tumors to be suppressed and raises the risk of getting cancer (1). The interaction of these genetic factors with lifestyle choices and environmental exposures can further influence an individual’s overall susceptibility to breast cancer.
Reproductive History: Menarche, Menopause, and Pregnancies
Changes in reproductive history, such as starting menstruation early, going through menopause late, having a first full-term pregnancy late, or never breastfeeding, are linked to a higher risk of breast cancer because of long-term exposure to hormones from within the body (14). Specifically, nulliparity and giving birth to a first child at an advanced age (after 35 years) are notable risk factors (15). These reproductive patterns prolong the hormonal impact on breast tissue, facilitating cellular proliferation and possibly elevating the risk of malignant transformation (1). On the other hand, longer breastfeeding and more exercise can lower the number of ovulatory cycles, which lowers overall estrogen exposure and lowers the risk of breast cancer (12).
Breast Density:
High mammographic breast density, defined by an elevated ratio of fibroglandular tissue to fatty tissue, serves as a robust and independent predictor of breast cancer risk (16). This higher density not only makes it harder to see possible tumors on mammograms, but it also means that there are more epithelial and stromal cells, which are more likely to turn cancerous (17). This higher number of cells creates a better environment for neoplastic growth and makes it harder to find tumors early (18).
Lifestyle and Controllable Factors (Modifiable)
These elements, unlike non-modifiable factors, can be influenced by individual choices and interventions, offering avenues for breast cancer prevention and risk reduction (19).
Hormone Replacement Therapy (HRT):
The use of hormone replacement therapy, especially combined estrogen-progestin regimens, has consistently been associated with a heightened risk of breast cancer, highlighting the significant role of exogenous hormones in mammary carcinogenesis (20). This increased risk is due to the hormones’ ability to stimulate the growth of breast epithelial cells, which can speed up the growth of existing subclinical cancers or cause new neoplastic changes. The duration and specific type of hormone replacement therapy (HRT), along with individual genetic predispositions, influence this risk, necessitating personalized risk-benefit assessments prior to commencement (21). Both endogenous and exogenous estrogens are linked to breast cancer risk, with oral contraceptives and hormone replacement therapy (HRT) serving as principal sources of exogenous estrogen (18).
Oral Contraceptives:
The duration of use, hormonal dosage, and individual susceptibility must all be taken into account, as these factors can collectively affect the overall risk profile, even though the increased risk associated with oral contraceptive use is typically small. Some research indicates that short-term hormone replacement therapy may not substantially affect breast cancer risk, regardless of the specific HRT formulation (22).
However, some progestins, when used with estrogen in hormone replacement therapy, have been shown to raise the risk of breast cancer more than estrogen alone (1). However, stopping the use of oral contraceptives usually causes this higher risk to slowly go down, and after a few years, it goes back to normal levels (23). The effect of oral contraceptives on breast cancer risk is contingent upon the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (23). This intricate relationship highlights the complexity of hormonal influences on breast carcinogenesis and underscores the necessity for personalized risk assessments when evaluating contraceptive options (24).
Alcohol Consumption: A Dose-Dependent Link
There is a direct link between drinking alcohol and a higher risk of breast cancer. Studies show that even moderate drinking raises the risk (18). This link is especially strong in breast cancers that have estrogen receptors and in women who have already gone through menopause. For every 10g of alcohol consumed daily, the risk goes up by 10.5% (25). Acetaldehyde, a byproduct of ethanol metabolism, and higher levels of estrogen are thought to be involved in the mechanisms that cause cancer. Both of these things can damage DNA and cause cells to grow in ways that are not normal (26).
Weight and Body Composition: The Impact of Obesity
Obesity, particularly postmenopausal obesity, is a recognized risk factor for breast cancer, primarily attributable to elevated estrogen synthesis in adipose tissue and persistent low-grade inflammation (27). Insulin resistance and hyperinsulinemia, which are common conditions that go along with obesity, make this higher risk even higher. These conditions help tumors grow by using different signaling pathways (28). Adipocytes in the breast microenvironment can provide free fatty acids to breast cancer cells, facilitating their proliferation and migration (29). Moreover, a higher body mass index correlates with an elevated risk of breast cancer, especially in postmenopausal women, highlighting a significant interaction between BMI and menopausal status (30).
Physical Activity: How Exercise Lowers Risk
Consistent physical activity has been demonstrated to lower breast cancer risk by modulating various biological pathways, including hormonal regulation, immune function, and inflammatory responses (31) (32). Additionally, physical activity can influence insulin-like growth factor signaling and enhance cellular energy metabolism, thus reducing pro-carcinogenic pathways (7). This protective effect is evident across a range of exercise intensities and durations, indicating that even moderate physical activity can provide considerable advantages in breast cancer prevention (33).
Factors with Uncertain or Debated Links
These factors, unlike those with established causal links, lack conclusive evidence to definitively classify them as either modifiable risk factors or protective elements, requiring further rigorous investigation.
Dietary Choices: The Evidence on Fat and Sugar
Although a direct causal relationship between dietary fat and sugar consumption and breast cancer risk is not yet established, emerging evidence indicates that specific dietary patterns, particularly those characterized by elevated saturated fat and refined sugar intake, may indirectly affect risk through mechanisms such as chronic inflammation, insulin resistance, and obesity (28). Moreover, the effects of particular macronutrient ratios and the overall glycemic load of the diet are under continuous investigation to clarify their exact contributions to mammary carcinogenesis.
Environmental Exposures: Chemicals and Pollutants
Ongoing investigations examine the role of pervasive environmental carcinogens, such as specific pesticides, industrial chemicals, and air pollutants, in the etiology of breast cancer through the disruption of endocrine function or the induction of DNA damage. These exposures can lead to epigenetic alterations and genetic mutations, collectively contributing to an increased propensity for malignant transformation within breast tissue.
Stress and Emotional Well-being
Although a direct causal relationship between psychological stress and the onset of breast cancer is predominantly unsubstantiated, chronic stress may indirectly influence cancer progression via immunosuppression and modified hormonal regulation. This complex interaction between psychological factors and physiological responses requires additional investigation to comprehensively understand its implications for breast cancer prognosis and patient management.
Conclusion
In summary, breast cancer etiology is multifactorial, encompassing a complex interplay of unavoidable genetic predispositions, hormonal influences, and modifiable lifestyle choices, each contributing to an individual’s overall risk profile.
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