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Title page for ETD etd-03232018-172621


Type of Document Dissertation
Author Ludwik, Katarzyna Anna
Author's Email Address katarzyna.a.ludwik@vanderbilt.edu
URN etd-03232018-172621
Title RSKy Business in the Mammary Gland
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Alissa Weaver Committee Chair
Andries Zijlstra Committee Member
Christopher Wright Committee Member
Deborah Lannigan Committee Member
Ian Macara Committee Member
Thomas Stricker Committee Member
Keywords
  • breast cancer
  • mammary gland
  • RSK2
  • estrogen receptor
Date of Defense 2018-03-12
Availability restricted
Abstract
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 signal–regulated kinase 1/2 (ERK1/2) and subsequently RSK2 are necessary for maintenance of ER 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.

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