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

BioRxiv : the Preprint Server for Biology
Monish R MakenaRajini Rao


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 S...Continue Reading

Related Concepts

Dendrite of Motor Neuron
CAP2 gene
In Vivo
Carboxy-Terminal Amino Acid
Motor Skills

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.