Abstract
Cumulative exposure to estrogen (E) and progesterone (P) over the menstrual cycle significantly influences the risk of developing breast cancer. Despite the dogma that PR in the breast merely serves as a marker of an active estrogen receptor (ER), and as an inhibitor of the proliferative actions of E, it is now clear that in the breast P increases proliferation independently of E action. We show here that the progesterone receptor (PR) and ER are expressed in different epithelial populations, and target non-overlapping pathways in the normal human breast. In breast cancer, PR becomes highly correlated with ER, and this convergence is associated with signaling pathways predictive of disease metastasis. These data challenge the established paradigm that ER and PR function co-operatively in normal breast, and have significant implications not only for our understanding of normal breast biology, but also for diagnosis, prognosis and/or treatment options in breast cancer patients.
Highlights
Cumulative exposure to estrogen (E) and progesterone (P) throughout a woman’s reproductive life significantly influences the overall risk of developing breast cancer [1], and the evidence that ovarian hormones are major drivers of breast cancer risk is irrefutable [2, 3]
In a cohort of normal human breast samples (22 independent samples from 20 patients), we revealed extensive heterogeneity in the combined expression of these steroid hormone receptors (HR) in HR+ cells, both within the same breast, and between individual samples (Figure 1A and Supp Fig 1A)
This study demonstrates that in the normal human breast, the expression of estrogen receptor (ER) and progesterone receptor (PR) do not correlate and that their functions are largely non-overlapping
Summary
Cumulative exposure to estrogen (E) and progesterone (P) throughout a woman’s reproductive life significantly influences the overall risk of developing breast cancer [1], and the evidence that ovarian hormones are major drivers of breast cancer risk is irrefutable [2, 3]. Ovariectomy decreases breast cancer risk, while early menarche, late menopause, and late first full-term pregnancy are associated with an increase in breast cancer risk [4]. Expression of the nuclear receptors, estrogen receptor (ER) and progesterone receptor (PR), through which E and P exert their effects, supports the view that these hormones have distinct roles in normal human breast [8, 9]. There is increasing evidence that full-term pregnancy induces long-term gene expression changes in the breast [15], with parous individuals displaying lower expression of ER and PR than nulliparous subjects [16,17,18]
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