Etiology of Hormone Receptor–Defined Breast Cancer: A Systematic Review of the Literature

Abstract

Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor–defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor–positive than hormone receptor–negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor–defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.

Mediation of Racial and Ethnic Disparities in Estrogen/Progesterone Receptor–Negative Breast Cancer by Socioeconomic Position and Reproductive Factors

“…Greater parity and earlier timing of offspring are associated with a lower risk of hormone receptor-positive breast cancer (13,15,24,25). Risk of ER/PR-positive breast cancer might be reduced by higher parity through several potential mechanisms, including changing profiles of circulating reproductive hormones and terminal differentiation of mammary epithelium, rendering the breast less susceptible to carcinogenic influences.…”

Potential Mechanisms by which Glucocorticoids Induce Breast Carcinogenesis through Nrf2 Inhibition

“…Although several genetic factors have been identified in breast cancer, most cases are attributed to environmental factors. At least, it is widely accepted that among risk factors, prolonged exposure to high levels of estrogen plays an important role in the initiation and development of breast cancer [141]. Indeed, studies in experimental animal models and cultured human cells strongly suggest that estradiol (E2), its interconvertible metabolite estrone (E1), and their estrogen quinones exert carcinogenic effects on breast tissue through several mechanisms [142].…”

Associations Between Serum Reproductive Hormone Concentrations and Hormonal Receptor Status Among Postmenopausal Chinese Women With Breast Cancer: An Observational Study

“…ER and PR are the most widely studied markers in breast cancer ( 28 ), and their expression levels are used as predictive markers of response to endocrine therapy ( 29 ). This study assessed the effects of postmenopausal on ER and PR expression in breast cancer and found that ER and PR expression were significantly associated with postmenopausal duration.…”