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Unexpected Impact of a Hepatitis C Virus Inhibitor on 17?-Estradiol Signaling in Breast Cancer.

ABSTRACT: 17?-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor ? (ER?). E2:ER? signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ER? abundance. Indeed, the control of ER? levels is necessary for the effects of E2, and E2 itself induces ER? degradation and cell proliferation in parallel. Thus, the modulation of intracellular ER? levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ER? levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ER? levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its effect on E2:ER? signaling has not been investigated. Here, for the first time, we analyzed the effects of Tel on intracellular ER? levels and E2:ER? signaling to cell proliferation in different ER?-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ER? levels, deregulates E2:ER? signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC.

SUBMITTER: Bartoloni S

PROVIDER: S-EPMC7279444 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Unexpected Impact of a Hepatitis C Virus Inhibitor on 17β-Estradiol Signaling in Breast Cancer.

Bartoloni Stefania S Leone Stefano S Acconcia Filippo F

International journal of molecular sciences 20200512 10

17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E ...[more]

PMID: 32408555

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Project description:BackgroundDue to the lack of ER?, triple negative breast cancers (TNBCs) are not susceptible to endocrine therapy using antiestrogens. However, the majority of TNBCs express the membrane bound estrogen receptor GPR30. We have recently shown that knock-down of GPR30 expression prevented growth stimulation of TNBC cell lines by 17?-estradiol. Now we analyzed whether specific inhibition of GPR30 represents a new option for therapy of TNBC.MethodsGrowth of TNBC cells was assessed using Alamar-blue colorimetric assay. Activation of c-Src and EGF-receptor was assessed using Western blots. Expression of c-fos, cyclin D1 and aromatase was quantified by RT-PCR. G?-specific signaling of GPR30 was analyzed by electrophoretic mobility shift assay.ResultsHCC1806 cells showed the highest GPR30 expression, in HCC70 cells it was clearly lower, in MDA-MB-231 cells it was lowest. 10-8 M 17?-estradiol significantly increased proliferation of HCC1806 cells to 134 ± 12% of control (p < 0.01). Proliferation of HCC70 cells was slightly increased to 116 ± 8% of control. Estriol significantly reduced cell number of HCC1806 cells to 16 ± 12% (p < 0.01). Cell number of HCC70 cells and of MDA-MB-231 cells was reduced to 68 ± 25% and to 61 ± 10%, respectively.Activity of Src kinase increased to 150 ± 10% (p < 0.05) by 10-8 M 17?-estradiol treatment in HCC1806 and to 220 ± 20% in HCC70 cells (p < 0.01). Estriol treatment completely inhibited 17?-estradiol-induced p-src activation. Transactivation of EGF-receptor increased by estradiol treatment to 350% in HCC1806 and to 280% in HCC70 cells. Estriol completely suppressed EGF-receptor transactivation. c-fos expression increased to 260% and to 190%, respectively. Estriol reduced this induction to 160% (HCC1806) and below control in HCC70 cells. Cyclin D1 was induced to 290% (HCC1806) and 170% (HCC70) and completely inhibited by estriol. 17?-estradiol increased CREB-phosphorylation to 400%. Binding of phospho-CREB to a CRE of cyclin D1 was enhanced to 320%.ConclusionSpecific pharmacological inhibition of GPR30 might become a promising targeted therapy for TNBC in future.

Dataset Information

Unexpected Impact of a Hepatitis C Virus Inhibitor on 17?-Estradiol Signaling in Breast Cancer.

Publications

Unexpected Impact of a Hepatitis C Virus Inhibitor on 17β-Estradiol Signaling in Breast Cancer.

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