Regulation of Breast Cancer Progression by Small G Proteins

Abstract

Breast cancer (BC) is the second leading cause of cancer-associated mortality among U.S. women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due to the lack of targeted treatment options. Management remains fixed in time with toxic chemotherapy developed in the 1960s as the only systemic treatment. An urgent and unmet need exists to identify new molecular targets for the treatment of TNBC. We identified RALA as a gene of interest and potential therapeutic target. Analysis of gene expression data and patient tissue arrays indicate elevated RALA is significantly associated with poor patient outcome. RalA is a small GTPase implicated in tumor proliferation, survival, and metastasis in a variety of cancers, although little is known of its role in BC. The necessity of RalA in TNBC progression was evaluated by its depletion in murine, MVT1, and human, MDA-MB-231, TNBC cell lines. In vitro, cell migration, proliferation, and nonadherent cell growth assays validated a pro-tumorigenic role for RalA in TNBC. Knockdown of RalA inhibited orthotopic primary tumor growth and metastasis of both MVT1 and MDA-MB-231 cells in vivo. To explore the potential of drug intervention, MVT1 and MDA-MB-231 were treated with BQU57, a small molecule Ral inhibitor. In vitro treatment hindered growth and a greater than additive effect was observed in combined treatment with paclitaxol. Further, BQU57 was effective in delaying orthotopic mammary tumor growth as well as lung metastasis and hindered the subcutaneous growth of a patient-derived xenograft model of metastatic TNBC. Together, these data demonstrate an important role for RalA in the pathogenesis of TNBC, exhibit the potential of Ral inhibitors as treatments for advanced TNBC, and advocate further investigation of RalA as a target for the precise treatment of metastatic TNBC. Ongoing investigations seek to determine the molecular mechanisms behind RalA's tumor and metastasis-promoting functions and the development of Ral inhibitors unique to RalA.