Endocrine Abstracts

Breast cancer is the most common oncology-related cause of death in women worldwide. The use of progestins in combined hormone replacement therapy (HRT) has been implicated in increasing the risk of developing breast cancer in postmenopausal women. Since various progestins are available for clinical use, all differentiated by structure, it is possible that not all progestins would lead to increased breast cancer risk. Progestins are synthetic ligands of the progesterone receptor (PR), designed to mimic the actions of natural progesterone. Although the PR exists as two isoforms, PR-A and PR-B, studies investigating the role of the PR in breast cancer seldom distinguish between the two isoforms. This is important, as the isoforms are functionally distinct and present in equimolar concentrations in the normal breast, while PR-A is overexpressed in breast cancer. The current study investigated the role of PR-A and PR-B in mediating progestin-induced regulation of genes involved in breast cancer biology, as well as their respective roles in physiological processes involved in breast cancer development and progression. In addition, effects of overexpression of PR-A relative to PR-B on the above-mentioned responses, was also investigated. Results showed differential regulation of genes by progestins via the individual PR isoforms. Moreover, effects on physiological processes such as cell proliferation, apoptosis, migration and invasion were progestin- and isoform-specific. These results not only highlight the importance of studying effects of individual progestins, but also effects via the individual PR isoforms. Moreover, in the presence of most progestins, overexpression of PR-A relative to PR-B inhibited physiological processes involved in breast cancer development and progression, suggesting that enhanced PR-A expression may be a positive prognostic marker for breast cancer.