Abstract 5653: Increased expression of brain-specific serine/threonine-protein kinase BRSK2 contributes to breast cancer survival by enhancing autophagy under nutrient stress

Abstract

Abstract Aberrant expression of certain cancer-promoting genes is the associative factor of metastasis and cancer-related death. Autophagy is a highly conserved catabolic process that can be regulated by starvation or stress. Among several cellular stresses, hypoxia and nutrient stress can strongly activate autophagy-related genes. Autophagy plays dual roles in cancer; it can be pro-death or pro-survival. The ability of the cancer cells to survive long-term under stress is still a vast question to cancer researchers. The nutrient status of is sensed by LKB1 downstream kinases AMP-activated protein kinase (AMPK). Recent studies revealed that BRSK2 is one of the AMPK related kinases regulated by LKB1 is the activator of WIPI protein function as building blocks for the formation of the autophagosome. Brain-specific kinases 1 and 2 are highly expressed in the mammalian forebrain regulating neuronal polarity and have lower expression in the testis and pancreas. We identified BRSK2 as one of the top genes highly expressed in 10 primary breast cancer tissue with a record of future bone metastasis compared to 10 primary breast tumors with no metastasis record through RNA seq analysis. Our extended analysis using TCGA and METABRIC cohort data unfolded that BRSK2 is highly elevated in breast cancer tumors compared to control breast tissue (p< 0.001), mainly in stage IV patients compared to other stages (p= 0.01). Furthermore, we observed that BRSK2 is differentially expressed in various breast cancer cell lines, in contrast, no expression in nonmalignant breast epithelial cells (MCF10A). We selected MDA-231 and BT474 cell lines having relatively lower BRSK2 expression, and expressed BRSK2 ectopically to understand details about BRSK2-mediated autophagy under nutrient stress. Interestingly, we observed that BRSK2 augmented nutrient starvation mediated autophagic flux in Triple-negative and ER/PR-positive breast cancer cell lines, along with elevated AKT, p-NF-kB, and STAT3 signaling pathways for survival under nutrient stress conditions. We further observed that several inflammatory cytokines CXCL1, CXCL6, TNF-α, and IL1-β, were significantly upregulated with BRSK2 overexpressed cells compared with the control cells. Knockdown of BRSK2 reduces autophagy and enhances apoptosis in breast cancer cells. Altogether, our data revealed that BRSK2 play a role in increasing autophagy to support cell survival under nutrient stress condition through AKT signaling pathways. Blocking of BRSK2 with inhibitor has reduced autophagy and increased apoptosis and cell death. Thus, BRSK2 can be a potential molecule as a therapeutic target for breast cancer metastasis. Citation Format: Nitai Hait, APARNA MAITI, Rongrong Wu, Kazuaki Takabe, Masanori Oshi. Increased expression of brain-specific serine/threonine-protein kinase BRSK2 contributes to breast cancer survival by enhancing autophagy under nutrient stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5653.