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Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion.

ABSTRACT: Multiple phosphorylation sites on the human estrogen receptor (hER)? were identified and shown to influence mammary carcinogenesis. In contrast, functional phosphorylation sites of hER? have yet to be experimentally identified and validated. Here, using mass spectrometry, we uncovered three serines (S75, S87, and S105) in the N-terminus of hER? as targets of ERK1/2 and p38 kinases. We raised a specific antibody against phosphorylated S105 (pS105) and demonstrated that this site was endogenously phosphorylated in MDA-MB-231 and BT-474 cells. A phospho-mimetic mutant generated from hER?1 was found to exhibit higher transactivation activity than hER?1. Ectopic expression of this mutant inhibited cell migration and invasion, but did not affect cell growth and cell-cycle progression in these cell models. In breast cancer specimens, pS105-hER? immunoreactivity was detected with a higher prevalence and intensity than that of hER?1. These results underscore the functional importance of the first experimentally identified hER?-phosphorylation site in breast cancer.

SUBMITTER: Lam HM

PROVIDER: S-EPMC3348253 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion.

Lam Hung-Ming HM Suresh Babu C V CV Wang Jiang J Yuan Yong Y Lam Ying-Wai YW Ho Shuk-Mei SM Leung Yuet-Kin YK

Molecular and cellular endocrinology 20120219 1

Multiple phosphorylation sites on the human estrogen receptor (hER)α were identified and shown to influence mammary carcinogenesis. In contrast, functional phosphorylation sites of hERβ have yet to be experimentally identified and validated. Here, using mass spectrometry, we uncovered three serines (S75, S87, and S105) in the N-terminus of hERβ as targets of ERK1/2 and p38 kinases. We raised a specific antibody against phosphorylated S105 (pS105) and demonstrated that this site was endogenously ...[more]

PMID: 22370157

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Project description:BackgroundEstrogen receptor β (ERβ) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERβ exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17β-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERβ in this process and the regulatory mechanisms involved.MethodsPolymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERβ and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERβ on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERβ/CLDN6/beclin1 expression in breast cancer patient samples.ResultsHere, E2 upregulated the expression of CLDN6, which was mediated by ERβ. ERβ regulated CLDN6 expression at the transcriptional level. ERβ inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERβ and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues.ConclusionOverall, this is the first study to demonstrate that the inhibitory effect of ERβ on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade.

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Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion.

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Phosphorylation of human estrogen receptor-beta at serine 105 inhibits breast cancer cell migration and invasion.

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