A Ca<sup>2+</sup>-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

Dang, Donna K.; Makena, Monish R.; Llongueras, José P.; Prasad, Hari; Ko, Myungjun; Bandral, Manuj; Rao, Rajini

doi:10.1101/379586

Cited by 5 publications

(22 citation statements)

References 52 publications

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“…1N) and can elicit constitutive Ca 2+ entry ( Fig. S1L), similar to wild type SPCA2 18 . Thus, the ability of SPCA2 to elicit robust Ca 2+ entry and increase baseline cytoplasmic Ca 2+ levels, independent of ion pumping activity, may drive cell proliferation.…”

Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 70%

“…1L). Expression of mutant D379N in MDA-MB-231 cells which have low endogenous SPCA2 levels 18 (Fig. S1K) increased cell proliferation, similar to wild type SPCA2 ( Fig.…”

Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 71%

“…Expression of SPCA2 is greatly elevated in the majority of breast cancer subtypes, including ER+, PR+ and HER2+ breast cancer cell lines and tumors 2,14,18 , where it confers poor patient survival prognosis ( Fig. S1A).…”

Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 99%

“…Key regulators of Ca 2+ homeostasis, including ion channels and pumps, show subtype-specific dysregulation in breast cancer, offering the potential of tailored intervention as a therapeutic option 2,9,32 . The secretory pathway Ca 2+ , Mn 2+ -ATPase Isoform 2 (SPCA2) is prominently elevated in luminal breast cancer subtypes that express ER, PR or HER2 receptors where it interacts with plasma membrane ion channels to elicit constitutive, store-independent Ca 2+ entry 2,18 . Ca 2+ influx is critical for several steps in cell cycle progression, including the initiation of DNA synthesis and entry into S-phase 33 .…”

Section: Multiple Mechanisms Of Ca 2+ Entry Drive Cell Cycle Progressmentioning

confidence: 99%

“…We did not see visible contamination by mycoplasma. Since SPCA2 expression is regulated by cell density 18 , cells were maintained at 50-60% confluency in both knockdown experiments and controls. Although we used lentiviral transfection, resistant clones tended to appear after 2-3 passages, therefore all experiments used early passage cells.…”

Section: Cell Culturementioning

confidence: 99%

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

Makena

Mekile

et al. 2020

Preprint

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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 p53 WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca 2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca 2+ -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 Ca 2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 or depletion of extracellular Ca 2+ 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+ p53 WT breast tumors drives pro-survival and chemotherapy resistance by suppressing the DNA damage response. Drugs that target storeindependent Ca 2+ entry pathways may have therapeutic potential in treating receptor positive breast cancer.

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Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 70%

“…1L). Expression of mutant D379N in MDA-MB-231 cells which have low endogenous SPCA2 levels 18 (Fig. S1K) increased cell proliferation, similar to wild type SPCA2 ( Fig.…”

Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 71%

Section: Spca2 Drives Cell Cycle Progression and Survivalmentioning

confidence: 99%

Section: Multiple Mechanisms Of Ca 2+ Entry Drive Cell Cycle Progressmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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

Makena

Mekile

et al. 2020

Preprint

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Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Makena

Dang

et al. 2020

Preprint

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The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.Simple SummaryThe triple receptor negative breast cancer subtype, or TNBC, currently has no tailored treatment options. TNBC is highly metastatic, associated with high patient mortality, and disproportionately occurs in Black/African American women where it contributes to racial disparities in health outcomes. Therefore, we focused on new therapeutic approaches to TNBC. We discovered that levels of the Calcium-ATPase SPCA2 are abnormally low in TNBC and that these low levels correlate with poor survival prognosis in patients. Previously, we showed that recombinant SPCA2 prevented TNBC cells from acquiring aggressive ‘mesenchymal’ properties associated with metastasis both in vitro and in vivo. These findings motivated us to search for drugs that turn the SPCA2 gene back on in TNBC cells. In this study, we show that histone deacetylase inhibitors increase SPCA2 levels, activate Ca2+ signaling and convert cancer cells to a less aggressive ‘epithelial’ state. These findings could lead to new treatment options for TNBC.Graphical Abstract

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Conservation of Epithelial-to-Mesenchymal Transition Process in Neural Crest Cells and Metastatic Cancer

Zhang

Aslam

Sharma

et al. 2021

Cells Tissues Organs

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Epithelial to mesenchymal transition (EMT) is a highly conserved cellular process in several species, from worms to humans. EMT plays a fundamental role in early embryogenesis, wound healing, and cancer metastasis. For neural crest cell (NCC) development, EMT typically results in forming a migratory and potent cell population that generates a wide variety of cell and tissue, including cartilage, bone, connective tissue, endocrine cells, neurons, and glia amongst many others. The degree of conservation between the signaling pathways that regulate EMT during development and metastatic cancer (MC) has not been fully established, despite ample studies. This systematic review and meta-analysis dissects the major signaling pathways involved in EMT of NCC development and MC to unravel the similarities and differences. While the FGF, TGFβ/BMP, SHH, and NOTCH pathways have been rigorously investigated in both systems, the EGF, IGF, HIPPO, Factor Receptor Superfamily, and their intracellular signaling cascades need to be the focus of future NCC studies. In general, meta-analyses of the associated signaling pathways show a significant number of overlapping genes (particularly ligands, transcription regulators, and targeted cadherins) involved in each signaling pathway of both systems without stratification by body segments and cancer type. Lack of stratification makes it difficult to meaningfully evaluate the intracellular downstream effectors of each signaling pathway. Finally, pediatric neuroblastoma and melanoma are NCC-derived malignancies, which emphasize the importance of uncovering the EMT events that convert NCC into treatment-resistant malignant cells.

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A Ca²⁺-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

Cited by 5 publications

References 52 publications

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

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

Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Conservation of Epithelial-to-Mesenchymal Transition Process in Neural Crest Cells and Metastatic Cancer

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A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

Cited by 5 publications

References 52 publications

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

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

Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Conservation of Epithelial-to-Mesenchymal Transition Process in Neural Crest Cells and Metastatic Cancer

Contact Info

Product

Resources

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A Ca²⁺-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

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

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