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Elevated estrogen receptor-? in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction.

ABSTRACT: Since loss of VHL is frequently detected early phase genetic event in human renal cell carcinoma, pVHL is assumed to be indispensable for suppression of tumor initiation step. However, induction of HIF-1?, target of pVHL E3 ligase, is more adequate to angiogenesis step after tumor mass formation. Concerning this, it has been reported that pVHL is involved in centrosome location during metaphase and regulates ER-? signaling. Here, we provide the evidences that pVHL-mediated ER-? suppression is critical for microtubule organizing center (MTOC) maintaining and elevated ER-? promotes MTOC amplification through disruption of BRCA1-Rad51 interaction. In fact, numerous MTOC in VHL- or BRCA1-deficient cells are reduced by Fulvestrant, inhibitor of ER-? expression as well as antagonist. In addition, we reveal that activation of ER signaling can increase ?-tubulin, core factor of TuRC and render the resistance to Taxol. Thus, Fulvestrant but not Tamoxifen, antagonist against ER-?, can restore the Taxol sensitivity in VHL- or BRCA1-deficient cells. Our results suggest that pVHL-mediated ER-? suppression is important for regulation of MTOC as well as drug resistance.

SUBMITTER: Jung YS

PROVIDER: S-EPMC4309251 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Elevated estrogen receptor-α in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction.

Jung Youn-Sang YS Chun Ho-Young HY Yoon Min-Ho MH Park Bum-Joon BJ

Neoplasia (New York, N.Y.) 20141201 12

Since loss of VHL is frequently detected early phase genetic event in human renal cell carcinoma, pVHL is assumed to be indispensable for suppression of tumor initiation step. However, induction of HIF-1α, target of pVHL E3 ligase, is more adequate to angiogenesis step after tumor mass formation. Concerning this, it has been reported that pVHL is involved in centrosome location during metaphase and regulates ER-α signaling. Here, we provide the evidences that pVHL-mediated ER-α suppression is cr ...[more]

PMID: 25499220

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Project description:BackgroundEstrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors.MethodsA genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis.ResultsEstrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.ConclusionsThis study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER.

Dataset Information

Elevated estrogen receptor-? in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction.

Publications

Elevated estrogen receptor-α in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction.

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