Abstract 5228: Mammary gland tumors in progesterone receptor transgenic mice

Abstract

Abstract The role of progesterone and its receptor, the progesterone receptor, in breast cancer remains controversial. Although years of clinical trial data have shown that synthetic progesterone (progestins) increases breast cancer risk, the role for native progesterone in breast cancer development is the source of much debate. PR is post-translationally modified, primarily through phosphorylation, by many mitogenic kinases, including ck2, cdk2 and MAPK. These phosphorylation events on PR dictate many aspects of PR biology, including promoter specificity and transcriptional co-factor interactions. Ck2, a mitogenic kinase shown to be upregulated in breast cancer, has been shown to phosphorylate PR and regulate transcription of a certain subset of PR target genes. In an effort to determine how this translates to murine mammary gland tumor formation, we created a bi-transgenic mouse overexpressing both PR and ck2 in the murine mammary gland. We studied long-term tumor formation in the PR/ck2 bi-transgenic mice, as compared to the single transgene controls (PR only or ck2 only), in both virgin and multiparous mice. Our preliminary data suggest a number of interesting results. First, tumor development is the highest in the PR transgenic mice, as compared to ck2 alone or PR/ck2 bi-transgenic mice. This is of particular interest as previous studies in PR transgenic mice failed to show mammary gland tumor formation, despite the presence of dysplastic mammary gland tissue. Moreover, the rate of tumor formation appears to be unaffected by parity: virgin and multiparous mice develop tumors at the same rate. This is in contrast to ck2 single-transgenic mice, where multiparty increases the rate of tumor formation (as observed by us and others). Interestingly, and most significantly to our studies, the combination of ck2 and PR appears to slow tumor formation rates as compared to either single transgenic mouse control. This phenotype is potentiated by pregnancy, as all multiparous PR/ck2 bi-transgenic animals still remain tumor free. These data, while still preliminary, suggest that ck2-dependent modification of PR may prevent mammary gland tumor formation, suggesting that PR regulation of a subset of genes (those genes regulated by ck2-phopshorylation) may drive anti-proliferative, tumor-preventing gene programs. Citation Format: Katelin A. Gibson, Merit L. Goodman, Christy R. Hagan. Mammary gland tumors in progesterone receptor transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5228.