Progesterone receptor isoforms (PRA and PRB) are expressed at equal levels in normal mammary cells. However, alteration in PRA/PRB expression is often observed in aggressive
breast cancer suggesting differential contribution of PR
isoforms in
carcinogenesis. The mechanisms underlying such processes remain to be established mainly due to paucity of appropriate cellular models. To investigate the role of PR
isoforms and the impact of imbalanced PRA/PRB ratio in transcriptional regulation, we have generated an original human
breast cancer cell line conditionally expressing PRA and/or PRB in dose-dependence of non-
steroid inducers. We first focused on PR-dependent transcriptional regulation of the paracrine
growth factor gene
amphiregulin (AREG) playing important role in
cancer. Interestingly, unliganded PRA increases AREG expression, independently of
estrogen receptor, yet inhibitable by antiprogestins. We show that functional outcome of
epidermal growth factor (
EGF) on such regulation is highly dependent on PRA/PRB ratio. Using this valuable model, genome-wide transcriptomic studies allowed us to determine the differential effects of PRA and PRB as a function of hormonal status. We identified a large number of novel PR-regulated genes notably implicated in
breast cancer and
metastasis and demonstrated that imbalanced PRA/PRB ratio strongly impact their expression predicting poor outcome in
breast cancer. In sum, our unique cell-based system strongly suggests that PRA/PRB ratio is a critical determinant of PR target gene selectivity and responses to hormonal/
growth factor stimuli. These findings provide molecular support for the aggressive phenotype of breast
cancers with impaired expression of PRA or PRB.