Expression of calcium pumps is differentially regulated by histone deacetylase inhibitors and estrogen receptor alpha in breast cancer cells

Abstract

BackgroundRemodeling of Ca2+ signaling is an important step in cancer progression, and altered expression of members of the Ca2+ signaling toolkit including the plasma membrane Ca2+ ATPases (PMCA proteins encoded by ATP2B genes) is common in tumors.MethodsIn this study PMCAs were examined in breast cancer datasets and in a variety of breast cancer cell lines representing different subtypes. We investigated how estrogen receptor alpha (ER-α) and histone deacetylase (HDAC) inhibitors regulate the expression of these pumps.ResultsThree distinct datasets displayed significantly lower ATP2B4 mRNA expression in invasive breast cancer tissue samples compared to normal breast tissue, whereas the expression of ATP2B1 and ATP2B2 was not altered. Studying the protein expression profiles of Ca2+ pumps in a variety of breast cancer cell lines revealed low PMCA4b expression in the ER-α positive cells, and its marked upregulation upon HDAC inhibitor treatments. PMCA4b expression was also positively regulated by the ER-α pathway in MCF-7 cells that led to enhanced Ca2+ extrusion capacity in response to 17β-estradiol (E2) treatment. E2-induced PMCA4b expression was further augmented by HDAC inhibitors. Surprisingly, E2 did not affect the expression of PMCA4b in other ER-α positive cells ZR-75-1, T-47D and BT-474. These findings were in good accordance with ChIP-seq data analysis that revealed an ER-α binding site in the ATP2B4 gene in MCF-7 cells but not in other ER-α positive tumor cells. In the triple negative cells PMCA4b expression was relatively high, and the effect of HDAC inhibitor treatment was less pronounced as compared to that of the ER-α positive cells. Although, the expression of PMCA4b was relatively high in the triple negative cells, a fraction of the protein was found in intracellular compartments that could interfere with the cellular function of the protein.ConclusionsOur results suggest that the expression of Ca2+ pumps is highly regulated in breast cancer cells in a subtype specific manner. Our results suggest that hormonal imbalances, epigenetic modifications and impaired protein trafficking could interfere with the expression and cellular function of PMCA4b in the course of breast cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4945-x) contains supplementary material, which is available to authorized users.

Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF‑7 breast cancer cells

“…The second most enriched KEGG pathway was the ‘calcium signaling pathway’, the mechanism of which is rather complicated in breast cancer. Previous studies have reported that the calcium signaling pathway interacts with other pathways to contribute to the onset and progression of breast cancer (64–68). In invasive ductal carcinoma the calcium signaling pathway was reported to interact with pathways in cancer, including the pathways of glyoxylate and dicarboxylate metabolism, basal transcription factors, tyrosine metabolism, FcγR-mediated phagocytosis, metabolism of xenobiotics by cytochrome P450 and phagosome (69).…”

Light-controlled calcium signalling in prostate cancer and benign prostatic hyperplasia

“…Varga et.al contemplate and demonstrate that in the upregulation of HDAC inhibitors, protein articulation of Ca 2+ pumps in an assortment of breast cancer cell lines uncovered low PMCA4b articulation in the ER-α-positive cells. So, we can say that Ca 2+ pump levels shape the intracellular Ca 2+ signals that influence a few downstream flagging pathways which might be valuable to treat BPH or prostate cancer [92]. Due to the depletion of ER calcium stores, the advancement of photoswitchable HDAC inhibitors is assumed to have a major role for HDAC inhibitor development with lesser side effects [93].…”

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

“…Thus, histone deacetylase inhibitors (HDACi) restore expression of tumor suppressor or endocrine target genes [13,25,26] and are being evaluated singly or in combination in clinical trials for the treatment of TNBC/metastatic cancers [8,27,28]. Indeed, epigenetic modulators have been reported to regulate expression of other members of the Ca 2+ -ATPase family [11].…”

“…Alteration in calcium signaling resulted in reactivation of tumor suppressor genes in cancer cells [10]. Some HDACi reportedly regulate intracellular Ca 2+ levels [11]. At clinically relevant drug concentrations, HDACi have been reported to elevate expression of E-cadherin, while suppressing several mesenchymal genes, thereby decreasing migration in vitro and metastasis in vivo in triple negative breast cancer cell lines [12][13][14][15][16].…”