Cooperation between oncogenic NRF2 and wild-type HRAS promotes progression of breast cancer

Abstract

HRAS is often overactivated in breast cancer, whereas mutations are rare in this malignancy. This study was aimed to determine how overexpressed wild-type HRAS (HRAS^WT) plays an oncogenic role in human breast cancer progression. The activated form of non-mutagemic HRAS^WT is highly overexpressed in aggressive triple-negative breast cancer (TNBC) compared with less invasive luminal breast tumor as well as normal mammary tissues. A qPCR assay showed that TNBC cells selectively overexpress HRAS^WT. Notably, HRAS directly interacted with and stabilized NRF2 whereas KRAS barely bound to NRF2. Further, HRAS^WT exerted its oncogenic capability by inducing interaction between NRF2 and STAT3. Such interaction was observed in TNBC tissues, but not other subtypes of breast cancer. Combined silencing of NRF2 and STAT3 suppressed TNBC growth to a greater extent than that achieved with single knockdown of individual genes. RNA sequencing analysis revealed expression profiles for genes related to cell migration which may account for synergistic oncogenic activity of NRF2 and STAT3. Our results suggest that NRF2 is a potential effector of HRAS that regulates downstream signaling in a KEAP1-independent manner. Non-mutated HRAS overexpression, in cooperation with NRF2, promotes the progression of breast carcinoma and might represent a novel therapeutic target against TNBC.

Keywords: NRF2; Nonmutated HRAS; Redox balance; STAT3; Triple-negative breast cancer.