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bioRxiv · 10.1101/2020.04.06.027946

Store Independent Ca2+ Entry Regulates the DNA Damage Response in Breast Cancer Cells

Makena, M. R.·Ko, M.·Mekile, A. X.·Dang, D. K.·Warrington, J. M.·Buckhaults, P. J.·Talbot, C.·Rao, R.
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Abstract

Although the mainstay of treatment for hormone responsive breast tumors is targeted endocrine therapy, many patients develop de novo or acquired resistance and are treated with chemotherapeutic drugs. The vast majority (80%) of estrogen receptor positive tumors also express wild type p53 protein that is a major determinant of the DNA damage response. Tumors that are ER+ and p53WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca2+-ATPase, SPCA2. In luminal ER+/PR+ breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. Independent of ion pump activity, SPCA2 elevates baseline Ca2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 or depletion of extracellular Ca2+ increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Consistent with these findings, SPCA2 knockdown confers chemosensitivity to DNA damaging agents including doxorubicin, cisplatin and ionizing radiation. We conclude that elevated SPCA2 expression in ER+ p53WT breast tumors drives pro-survival and chemotherapy resistance by suppressing the DNA damage response. Drugs that target storeindependent Ca2+ entry pathways may have therapeutic potential in treating receptor positive breast cancer.

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Makena, M. R., Ko, M., Mekile, A. X., Dang, D. K., Warrington, J. M., Buckhaults, P. J., Talbot, C., Rao, R.. 2020-04-07. Store Independent Ca2+ Entry Regulates the DNA Damage Response in Breast Cancer Cells. https://doi.org/10.1101/2020.04.06.027946

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