Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells

The ovarian hormone progesterone is essential for normal breast development and function. However, it is also implicated in breast cancer development. Progesterone signals through two nuclear receptors [progesterone receptor A (PRA) and progesterone receptor B (PRB)], which display striking differences in transcriptional activity when analyzed separately. The two species are coexpressed equally in normal breast, but expression becomes markedly disrupted in breast cancer, where a predominance of PRA is common. To determine the impact on PR transcriptional activity of the shift from coexpression of PRA and PRB, observed in normal cells, to predominance of PRA, common in cancers, we modeled these changes in PR expression patterns using an inducible model of PRA predominance. At short treatment times progestin regulation was directed toward transcriptional modulators, whereas longer exposure more frequently targeted genes associated with regulation of cell shape, adhesion, and metabolism, and a number of these targets acquired responsiveness only when PRA predominance was achieved. Consistent with this, overexpression of PRA altered progestin effects on cell-substrate attachment and focal adhesion signaling. Our data suggest that disrupted balance of PRA and PRB remodels progestin responsiveness and that altered regulation of morphology and adhesion are important components of altered progestin response in breast cancer.