The treatment of BLBC represents an unmet medical need. Wu et al. show that AKR1B1 facilitates BLBC progression through a positive feedback loop that activates the EMT program, suggesting that inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC.
Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood.Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca2+-NFAT1 axis, and cancer cell behavior were assessed by Ca2+ imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model.Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca2+ concentration by activating GABA-A receptor (GABAA), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca2+-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance.Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca2+-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease.
Basal-like breast cancer (BLBC) is associated with a poor clinical outcome due to the few treatment options and absence of effective targeted agents. Here, we show that malic enzyme 1 (ME1) is dramatically upregulated in BLBC due to ME1 copy number amplification. ME1 expression increases glucose uptake and lactate production, and reduces oxygen consumption, leading to aerobic glycolysis. ME1 expression promotes, whereas knockdown of ME1 expression suppresses tumorigenicity. In breast cancer patients, ME1 expression is positively correlated with large tumor size, high grade, poor survival, and chemotherapy resistance. Our study not only contributes to a new understanding of how metabolic reprogramming contributes to BLBC progression, but also provides a potential prognostic marker and therapeutic target for this challenging disease.
Cao et al. show that UGT8 promotes BLBC progression through activating sulfatide–αVβ5 axis. ZA is identified as a direct inhibitor of UGT8 and suppresses BLBC progression, suggesting that inhibition of UGT8 offers a promising opportunity for treating BLBC.
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