Abstract
Breast cancer (BC) is the most diagnosed cancer and the second leading cause of cancer death in American
women. Triple negative breast cancer (TNBC) accounts for 15% to 20% of all BC cases and has the worst
prognosis and overall survival. Although many targeted agents are ongoing clinical trials, none have significantly
improved the survival in TNBC patients. Thus, the identification of novel targets and effective strategies, including
combination therapies, are urgent needed for TNBC patients. PRMT5 is emerging as a potential therapeutic
target. Several PRMT5 inhibitors have been developed and are currently being evaluated in clinical trials,
including a phase II trial for early-stage BC. Compared to other BC subtypes, TNBC displays the strongest
PRMT5 expression. High PRMT5 expression is positively correlated with poorer survival rate in TNBC patients.
Despite its association with TNBC progression, PRMT5 regulation and the molecular mechanisms by which
PRMT5 promotes TNBC remain elusive. Moreover, TNBC cell lines display differential sensitivity or resistance
to PRMT5 inhibitors, but the mechanisms have yet to be defined. Our preliminary studies demonstrate that: (1)
PRMT5 is ubiquitinated by E3 ubiquitin ligase TRAF6, which is important for its activation and TNBC cell
proliferation; (2) PRMT5 suppresses autophagy induction and catalyzes ULK1 arginine methylation; and (3)
autophagy inhibition sensitizes TNBC cells to PRMT5 inhibitor. Based on these preliminary findings, we propose
three aims to test our central hypothesis that TRAF6, PRMT5, and ULK1 form a novel axis to regulate autophagy
and TNBC progression, and combination of PRMT5 and autophagy inhibitors is a potential strategy to combat
TNBC. To validate our hypothesis, we propose three Aims. In Aim 1, we will define the mechanism through which
TRAF6 regulates PRMT5 activation. In Aim 2, we will define the molecular function of PRMT5 in autophagy
regulation by methylating ULK1. In Aim 3, we will evaluate the synergistic effect of PRMT5 and autophagy
inhibitors in TNBC. We believe that our proposed studies will not only substantially advance current
understanding of regulatory mechanism and biological function of PRMT5, but also provide a rationale for
combination of PRMT5 and autophagy inhibitors to treat TNBC.