RR190090 — Cancer Prevention and Research Institute of Texas

Grant Information

Grant ID	RR190090
Awarded On	August 21, 2019
Title	Recruitment of First-Time, Tenure-Track Faculty Members
Program	CPRIT Scholar
Award Mechanism	Recruitment of First-Time, Tenure-Track Faculty Members
Institution/Organization	The University of Texas Southwestern Medical Center
Principal Investigator/Program Director	Benjamin Sabari
Cancer Sites	Breast, Prostate, Uterus
Contracted Amount	$2,000,000
Summary of Goals and Objectives	The objective of this proposal is to gain mechanistic insight into the role of Mediator-dependent condensate formation in ER+ breast cancer. The MED1 subunit of the Mediator complex is required for ER gene regulation, tumor formation, and resistance to therapy. I showed that MED1 forms phase-separated condensates at sites of gene activation. My hypothesis is that MED1 is required for estrogen-dependent gene activation because of its capacity to form condensates at ER target genes. Dissecting the molecular mechanism of MED1 phase separation promises to reveal new regulatory mechanisms with the potential to uncover novel avenues ... Read More The objective of this proposal is to gain mechanistic insight into the role of Mediator-dependent condensate formation in ER+ breast cancer. The MED1 subunit of the Mediator complex is required for ER gene regulation, tumor formation, and resistance to therapy. I showed that MED1 forms phase-separated condensates at sites of gene activation. My hypothesis is that MED1 is required for estrogen-dependent gene activation because of its capacity to form condensates at ER target genes. Dissecting the molecular mechanism of MED1 phase separation promises to reveal new regulatory mechanisms with the potential to uncover novel avenues for therapeutic intervention. Aim1: Characterize role of MED1 condensates in ER? gene regulation. I will develop MED1 mutants that are incapable of phase separating, then introduce mutant and wild-type proteins into breast cancer cell lines in the background of endogenous MED1 depletion and characterize the effect of estrogen signaling with or without tamoxifen. Aim2: Identify effectors of Mediator condensates in estrogen-stimulated breast cancer cells. Understanding the proteins concentrated within MED1 condensates will define a new class of effector proteins likely to play critical roles in ER?/MED1-mediated oncogenic gene activation. I will identify the effector proteins recruited by MED1 phase separation in ER+ breast cancer cell lines and characterize their role in ER?-driven gene expression. Aim3: Investigate the role of Mediator condensates in cell proliferation and tumor formation. Using an array of cell and xenograft models of breast cancer tumor formation, I will determine how the formation of MED1 condensates affects the estrogen-dependent activation of cell proliferation and its role in mechanisms of endocrine resistance. This aim will connect molecular aspects of MED1 phase separation to estrogen-dependent cancer-related outcomes. Read Less