The role of TRPV6 in breast carcinogenesis

Bolanz, Katrin A.; Hediger, Matthias A.; Landowski, Christopher P.

doi:10.1158/1535-7163.mct-07-0478

Cited by 184 publications

(179 citation statements)

References 38 publications

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“…Our former study confirmed that TRPV6 is expressed at higher levels in breast cancer samples compared with nontumorous samples (28). We also showed that TRPV6 expression in T47D breast cancer cells is increased by estrogen, progesterone, and 1,25-vitamin D3.…”

Section: Introductionsupporting

confidence: 83%

“…In addition, our laboratory recently showed that a knockdown of TRPV6 expression using siRNA decreased basal calcium influx and proliferation of T47D human breast cancer cells (28). As a novel finding, we also found that tamoxifen, at micromolar levels, inhibits TRPV6-mediated calcium influx in human TRPV6-expressing Xenopus oocytes.…”

Section: Discussionsupporting

confidence: 58%

“…It should be noted that we selected this initial tamoxifen concentration because the IC 50 value of tamoxifen was 7.5 μmol/L in Xenopus oocytes (28).…”

Section: Discussionmentioning

confidence: 99%

“…The studies indicated that it might be clinically useful to develop specific TRPV6 inhibitors as breast cancer drugs. Especially, in the case of ER-negative tumors, TRPV6 targeting could be promising (28).…”

Section: Introductionmentioning

confidence: 99%

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Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Bolanz

Kovács

Landowski

et al. 2009

Molecular Cancer Research

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The epithelial calcium channel TRPV6 is upregulated in breast carcinoma compared with normal mammary gland tissue. The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy. Previously, we showed that tamoxifen inhibits calcium uptake in TRPV6-transfected Xenopus oocytes. In this study, we examined the effect of tamoxifen on TRPV6 function and intracellular calcium homeostasis in MCF-7 breast cancer cells transiently transfected with EYFP-C1-TRPV6. TRPV6 activity was measured with fluorescence microscopy using Fura-2. The basal calcium level was higher in transfected cells compared with nontransfected cells in calcium-containing solution but not in nominally calcium-free buffer. Basal influxes of calcium and barium were also increased. In transfected cells, 10 μmol/L tamoxifen reduced the basal intracellular calcium concentration to the basal calcium level of nontransfected cells. Tamoxifen decreased the transport rates of calcium and barium in transfected cells by 50%. This inhibitory effect was not blocked by the estrogen receptor antagonist, ICI 182,720. Similarly, a tamoxifen-induced inhibitory effect was also observed in MDA-MB-231 estrogen receptor-negative cells. The effect of tamoxifen was completely blocked by activation of protein kinase C. Inhibiting protein kinase C with calphostin C decreased TRPV6 activity but did not alter the effect of tamoxifen. These findings illustrate how tamoxifen might be effective in estrogen receptor-negative breast carcinomas and suggest that the therapeutic effect of tamoxifen and protein kinase C inhibitors used in breast cancer therapy might involve TRPV6-mediated calcium entry. This study highlights a possible role of TRPV6 as therapeutic target in breast cancer therapy.

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Section: Introductionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 58%

“…It should be noted that we selected this initial tamoxifen concentration because the IC 50 value of tamoxifen was 7.5 μmol/L in Xenopus oocytes (28).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Bolanz

Kovács

Landowski

et al. 2009

Molecular Cancer Research

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“…It has been documented for half a century that low [Ca 2 þ ] induces colon cell proliferation in vitro and in vivo. 46,47 Although several recent studies have shown that TRPV6 overexpression is often associated with increased cell proliferation in colon, breast, and prostate cancers, [48][49][50] it is not clear how an increase in TRPV5/6 levels leads to elevated proliferation. The Ca 2 þ deficiency-induced and Trpv5/6-dependent IGF signaling unraveled by this study provides a possible mechanistic explanation for the elevated epithelial cell proliferation in Ca 2 þ deficiency.…”

Section: Discussionmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca 2 þ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca 2 þ -transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca 2 þ ] environments. BrdU pulse-labeling experiments suggest that low [Ca 2 þ ] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca 2 þ ] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca 2 þ -selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca 2 þ ]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca 2 þ ]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca 2 þ ]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca 2 þ ]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca 2 þ ]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca 2 þ ] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca 2 þ deficiency.

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NCS‐1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin

et al. 2019

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Neuronal calcium sensor-1 (NCS-1) is a positive modulator of IP 3 receptors and was recently associated with poorer survival in breast cancers. However, the association between NCS-1 and breast cancer molecular subtypes and the effects of NCS-1 silencing on calcium (Ca 2+ ) signaling in breast cancer cells remain unexplored. Herein, we report for the first time an increased expression of NCS-1 in breast cancers of the basal molecular subtype, a subtype associated with poor prognosis. Using MDA-MB-231 basal breast cancer cells expressing the GCaMP6m Ca 2+ indicator, we showed that NCS-1 silencing did not result in major changes in cytosolic free Ca 2+ increases as a result of endoplasmic reticulum Ca 2+ store mobilization. However, NCS-1 silencing suppressed unstimulated basal Ca 2+ influx. NCS-1 silencing in MDA-MB-231 cells also promoted necrotic cell death induced by the chemotherapeutic drug doxorubicin (1 µM). The effect of NCS-1 silencing on cell death was phenocopied by silencing of ORAI1, a Ca 2+ store-operated Ca 2+ channel that maintains Ca 2+ levels in the endoplasmic reticulum Ca 2+ store and whose expression was significantly positively correlated with NCS-1 in clinical breast cancer samples. This newly identified association between NCS-1 and basal breast cancers, together with the identification of the role of NCS-1 in the regulation of the effects of doxorubicin in MDA-MB-231 breast cancer cells, suggests that NCS-1 and/or pathways regulated by NCS-1 may be important in the treatment of basal breast cancers in women.

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The role of TRPV6 in breast carcinogenesis

Cited by 184 publications

References 38 publications

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

NCS‐1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin

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