Possible mechanisms for induced effect of gestagens to breast cancer risk at hormone therapy in contraception and postmenopause

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We were able to show in in vitro and in vivo studies, that the progesterone receptor membrane component-1 (PGRMC1) mediates estrogen receptor alpha (ERalpha) dependent proliferative effects to MCF-7 breast cancer cells. Therefore, PGRMC1 could be involved in tumourigenesis. This observation is of high clinical relevance since an increase of breast cancer risk was observed during gestagen-containing postmenopausal hormone therapy (HT). The mechanism underlying the proliferative effect of gestagens to breast cancer cells is unknown. Prospective observational studies suggest that the risk of developing breast cancer is dependent of the selected gestagen component.PGRMC1 exhibits several cytoplasmic binding sites for signal transduction proteins. In our preliminary work we observed that deletion of two phosphorylation sites for the casein kinase 2 (CK2), serine 56 and 180, eliminates the proliferative effect of gestagens. Our hypothesis is that phosphorylation of these serines may activate PGRMC1 and recruit several signal proteins.In this project, we will study the functional and clinical relevance of PGRMC1 in transmission of membrane-initiated gestagen signals. To achieve this aim we want to (1) analyse how the combination of several gestagens and PGRMC1-variants affect the proliferation and apoptosis of breast cancer cells, and (2) analyse the functional role of the putative interaction partners CK2, ERK1/2 and PDK1 on PGRMC1-signalling dependent to gestagen-binding.