Abstract 3461: RSK2 is a driver of estrogen receptor positive breast cancer

Abstract

Abstract For unknown reasons, high levels of active Ser/Thr protein kinase RSK in estrogen receptor α (ERα)-positive (ER+) breast cancer patients correlate with better responsiveness to anti-estrogen therapies. Investigation of these surprising observations led us to discover an unanticipated mechanism in which ERα controls RSK2 nuclear accumulation. RSK2 is retained in the nucleus by physical association with ERα and this interaction is disrupted by anti-estrogen treatment. Consistent with these findings, in primary human ER+ breast tissue organoids, 4-hydroxy-tamoxifen (4-OHT) drove export of RSK2 to the cytoplasm. Importantly, RSK2 nuclear accumulation is critical for the expression of the oncogene, cyclin D1. This conclusion is supported by the observations that a RSK2 mutant, which cannot accumulate in the nucleus, does not rescue cyclin D1 in cells silenced for endogenous RSK2. Analysis of RNAseq data shows that ERα and RSK2 cooperatively regulate a transcriptional program, which includes cyclin D1. The physiological relevance of these conclusions is supported by our observations that in ∼60% of ER+ breast cancer patients, active nuclear RSK correlates with ERα and cyclin D1 levels. Taken together, these findings suggest that responsiveness to endocrine-based therapy is driven by reduced RSK2 nuclear accumulation, which in turn reduces expression of cyclin D1 and of other tumor-promoting effectors. Based on these observations we hypothesized that nuclear RSK2 cooperates with ERα and is a physiologically relevant driver of ER+ breast cancer. To test this hypothesis we generated a transgenic mouse model in which the MMTV promoter controls expression of RSK2 fused with the nuclear localization signal (NLS) of SV40. Strikingly, in ∼50% of transgenic mice forced nuclear accumulation of RSK2 in the mammary gland caused hyperplasia and ductal carcinoma in situ (DCIS). These results are the first demonstration that RSK2 can drive proliferation and transformation in vivo. Transgenic animals had a 4-fold increase in the number of cyclin D1 expressing cells and a 6-fold increase in Ki67 levels. Surprisingly, in vivo expression of nuclear RSK2 expanded the population of ER+ cells. These results demonstrate, for the first time, that nuclear RSK2 drives the amplification of the cell population relevant to ER+ breast cancer. In agreement with these observations we found that overexpression of ERα in the mouse mammary gland expands exclusively, by ∼3 fold, the cell population that co-expresses ERα and active nuclear RSK. These results further support our hypothesis that RSK2 cooperates with ERα and is an important drug target for ER+ breast cancer. Citation Format: Katarzyna Ludwik, Deborah Lannigan. RSK2 is a driver of estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3461. doi:10.1158/1538-7445.AM2015-3461