Progesterone receptor-A in taxane treatment of breast cancer.

摘要

The taxanes, docetaxel and paclitaxel, are among the most effective treatments for metastatic breast cancer. Taxanes regulate genes in many cancers, however, little is known about genes regulated by taxanes in breast cancers. Also, while taxanes are clearly effective for metastatic breast cancers, it is unclear whether response to taxanes is influenced by presence of estrogen (ER) or progesterone (PR) receptors in tumors. It is known that increased expression of the PR-A isoform of PR in breast cancer has a more aggressive phenotype, and is the focus of these studies. These studies also focused on unliganded PR-A, known to regulate gene transcription, and mimicking a progesterone depleted state, such as menopause, when the incidence of ER+/PR+ breast cancer incidence is increased.;In an ER+/PR-A+ breast cancer model, presence of unliganded PR attenuates taxane-induced cell death. To determine mechanisms of PR mediated resistance to taxanes, expression profiling was performed in ER+ breast cancer cells engineered to inducibly express PR-A. Cells lacking or expressing PR-A for 48 hours were treated with vehicle, docetaxel or paclitaxel for 24 hours and gene expression profiling was performed. There is a complex relationship between taxane and PR-A regulated genes with some gene subsets regulated in the same direction, and others in the opposite direction by taxanes versus PR. Additionally, unliganded PR-A regulate multiple cell cycle and spindle assembly checkpoint genes that amplify or oppose the effects of taxanes. As a result, the presence of PR-A, even without progestins, modifies the ability of taxanes to regulate gene expression. Moreover, PR-A increase taxane-induced multinucleation both in vitro and in vivo in a xenograft model of breast cancer; an anomaly linked to taxane resistance. In fact, blockade of PR-A activity with a pure antiprogestin decreased multinucleation. In summary, these studies suggest that PR-A attenuate taxane-induced cell death by counter-regulating key taxane controlled genes and increasing multinucleation. We propose that combination therapy with pure antiprogestins may improve taxane responsiveness of PR-positive breast cancers.