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A complex interplay between the extracellular space, cytoplasm and individual organelles modulates Ca2+ signaling to impact all aspects of cell fate and function. In recent years, the molecular machinery linking endoplasmic reticulum stores to plasma membrane Ca2+ entry has been defined. However, the mechanism and pathophysiological relevance of store-independent modes of Ca2+ entry remain poorly understood. Here, we describe how the secretory pathway Ca2+-ATPase SPCA2 promotes cell cycle progression and survival by activating store-independent Ca2+ entry through plasma membrane Orai1 channels in mammary epithelial cells. Silencing SPCA2 expression or briefly removing 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 redox stress and chemosensitivity to DNA damaging agents. Unexpectedly, SPCA2-mediated Ca2+ entry into mitochondria is required for optimal cellular respiration and the generation of mitochondrial membrane potential. In hormone receptor positive (ER+/PR+) breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. We suggest that elevated SPCA2 expression could drive pro-survival and chemotherapy resistance in cancer cells, and drugs that target store-independent Ca2+ entry pathways may have therapeutic potential in treating cancer., Graphical abstract Image 1, Highlights • SPCA2 drives store independent Ca2+ entry (SICE) for cell survival and proliferation. • Silencing SPCA2 activates ROS, DNA damage and ATM/ATR-p53 axis. • SPCA2 confers chemoresistance to DNA damaging agents. • SPCA2 maintains mitochondrial Ca2+, membrane potential and respiration. • Store independent Ca2+ entry (SICE) is important for mitochondrial function.

SUMMARYAlthough 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 p53WTrespond 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+ p53WTbreast 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.

Despite being a major user of many technologies and innovations, the healthcare sector's role and influence as a procurer of technologies has been poorly represented by the literature and consequently is not fully understood. Providing a practical example of the introduction of digital signal process (DSP) hearing aids in to the English NHS, this paper discusses the role of public sector procurement agencies in the uptake of technologies from the private sector and their adoption by the public sector. Employing a system of innovation (SI) approach, the paper highlights the need for policy-makers to adopt a dynamic as well as systemic perspective that recognises the shifting roles, responsibilities and interactions of key stakeholders throughout the innovation process.