The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Here, we presented evidence that tamoxifen supports breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK Signaling. Tamoxifen enhances mitochondrial fusion under nutrition‐deprived conditions by suppressing Drp1 ser616 phosphorylation and upregulating Mfn1 levels. Tamoxifen‐induced mitochondrial fusion is mediated by the activation of AMPK, as evidenced by the pharmacological inhibition of AMPK reverse mitochondrial fusion. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates nutrition deprivation-induced endoplasmic reticulum stress by enhancing selective ER-phagy and specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion and ER-phagy by regulating stress kinase Signaling under nutrition deprivation conditions.

Funding: ICMR Grants