The family of ribosomal S6 Ser/Thr protein kinases (RSK) controls proliferation, viability and motility and, therefore, contributes to the etiology of numerous cancers, including breast. We found that RSK2 is an obligate partner in estrogen receptor alpha (ER)-driven breast cancer by physically interacting with ER to activate a pro-neoplastic transcriptional network. ER sequesters RSK2 in the nucleus and ER+ tumor growth is dependent on nuclear RSK2. In a novel mouse model, mammary-specific expression of nuclear RSK2 drives development of high grade ER+ ductal carcinoma in situ.
Besides being a driver in breast cancer, ER+ cells are indispensable for normal mammary gland function. Therefore, we investigated RSK2 contributions to mammary gland homeostasis. We discovered that activation of extracellular signalâregulated kinase 1/2 (ERK1/2) and subsequently RSK2 are necessary for maintenance of ERï¡ levels in the presence of estrogen. This protective mechanism is a part of a negative feedback loop, as estrogen positively regulates expression of growth factors that activate ERK1/2-RSK2 signaling. As ER degradation is intimately linked with its transcriptional activity, loss of RSK2 alters the transcriptome architecture in response to estrogen. Consequently, inappropriate hormonal responses cause increased DNA damage. Together, our findings indicate that RSK2 regulates ER-mediated processes in both breast cancer and in normal mammary epithelium.
In addition to ER+ breast cancer, RSK contributes to triple negative breast cancer (TNBC). Levels of active RSK are increased in ~70% of TNBCs and RSK regulates migration in TNBC. As TNBC patients have increased probability of death due to metastasis, we described an in vivo study showing the efficacy of RSK-targeting in metastatic TNBC. We found that RSK1 and RSK2 regulate metastatic colonization and growth suggesting that targeting RSK is a potential therapeutic strategy for metastatic breast cancer.
Development of targeted therapies for breast cancer is frequently hindered by the lack of in vitro models that recapitulate diverse tumor phenotypes. As tumor heterogeneity contributes to chemotherapy resistance and decreased patient survival, we developed an organoid culture system that recapitulates tumor heterogeneity. Our methodology focuses on quantifiable cellular phenotypes and provides a novel tool for drug-testing.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03232018-172621 |
| Date | 11 April 2018 |
| Creators | Ludwik, Katarzyna Anna |
| Contributors | Thomas Stricker, Deborah Lannigan, Alissa Weaver, Andries Zijlstra, Ian Macara, Christopher Wright |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03232018-172621/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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