The Role of the Secretory Pathway Ca2+-ATPase, SPCA2 in Breast Cancer Evolution
DANG-DISSERTATION-2018.pdf (28.91Mb) (embargoed until: 2022-05-01)
Dang, Donna K
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Calcium dysregulation in breast cancer can occur early during dysplasia in mammary tissue, and persist throughout the progression of cancer. This perturbation to the homeostasis of calcium can be detrimental to the normal physiology of a cell. To elucidate some of the consequences of this dysregulation, we investigate the role of the Golgi pumps, the secretory pathway Ca2+-ATPases, SPCA1 and SPCA2 in breast cancer. First, we examine the formation of microcalcifications, which are mineralized deposits of calcium hydroxyapatite crystals that form precipitates in the extracellular matrix (ECM). These radiographic signatures are early indicators of malignancy and the mechanisms by which they form have not been well studied. Our findings show that both SPCA isoforms are induced in an in vitro model of calcification, and that their pump activity is required to promote calcified deposits. We suggest that early in dysplasia increased SPCA gene expression is important to shuttle the components that make up hydroxyapatite within secretory vesicles en route to the ECM. SPCA2 specifically plays an important role in tumorigenesis and in promoting proliferation by mediating Ca2+ entry. Unlike the formation of microcalcifications, we show that pumping activity is not required for tumorigenesis. Knockdown of SPCA2 results in a decrease in growth, stalling the cell cycle at G0/G1 and activating the p53-signaling pathway. We discovered that SPCA2 is co-expressed with E-cadherin as an epithelial gene and is required for the biogenesis of E-cadherin. Loss of SPCA2 alters proper E-cadherin trafficking resulting in transcriptional induction of mesenchymal markers that characterize epithelial to mesenchymal transition (EMT). Breast cancer cells that undergo EMT can result in disease progression towards more aggressive cancers in later stages of breast cancer, thus promoting cancer evolution. In contrast to SPCA2, we show that SPCA1 is co-expressed with mesenchymal genes. We conclude that the SPCA isoforms can be utilized as markers to classify clinically significant cancer subtypes. Taken together, our studies provide valuable insight on understanding breast cancer progression, and identifies a novel target for personalized treatment.