Investigating GSTP1 as a novel regulator of the cysteine redoxome in breast cancer and maker of vulnerability to redox-based therapy

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Project Summary Glutathione S-transferase Pi 1 (GSTP1) is an enzyme that conjugates glutathione to small molecule electrophiles. GSTP1 has been implicated in promoting the growth of many cancer types where GSTP1 overexpression is proposed to promote metabolic re-wiring or sequester cancer-related signaling proteins through protein-protein interactions. In contrast to the modest upregulation of GSTP1 in cancer reported by these studies, our systematic evaluation of cancer cell lines, patient-derived xenografts, and patient tumors finds that GSTP1 expression is uniquely and dramatically silenced by many orders of magnitude in luminal breast cancer, going from one of the most abundant cellular proteins to barely express. Her2 positive (Her2+) breast cancers have a bimodal GSTP1 expression distribution, with a significant proportion also silencing GSTP1. Decreased GSTP1 expression in breast cancer allowed us to discover a novel, non-canonical regulatory function of GSTP1: re-directing the flux of cysteine oxidation to structurally remodel the proteome via allosteric disulfide bonds. These changes are critical for breast cancer transformation since re-expression of GSTP1 and inhibition of redox signaling decreases the transformation capacity of GSTP1-silenced breast cancer cells. This proposal focuses on two Specific Aims. First, is GSTP1 silencing a therapeutic vulnerability in BRCA? Second, what are the molecular and redoxomic consequences of GSTP1 silencing? Together, these Aims will provide new mechanistic insight into how GSTP1 expression drives redox signaling in breast cancer and determine if GSTP1 silencing is a therapeutically actionable vulnerability.