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Stable inhibition of specific estrogen receptor ? (ER?) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells.

ABSTRACT: Elevated phosphorylation of estrogen receptor ? (ER?) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ER? signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ER? signaling, resulting in aggressive ER?-independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ER?-specific short hairpin RNA that reduced endogenous ER?. The resulting cell line was stably transfected with wild-type ER? (ER-AB cells), or ER? containing serine to alanine mutation at S118 or S167 (S118A cells and S167A cells, respectively). These stable cell lines expressed approximately equivalent ER? compared with parental MCF-7 cells and were evaluated for growth, morphology, migration/invasion, and ER?-regulated gene expression. S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro. Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size, and both S118A and S167A cells exhibited less cellular complexity. S118A and S167A cells expressed pancytokeratin and membrane localization of ?-catenin and did not express vimentin, indicating retention of epithelial lineage markers. Expression of ER?-target genes and other genes regulated by ER? signaling or involved in breast cancer were markedly altered in both S118A and S167A cells. In summary, attenuated phosphorylation of ER? at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells, resulting in increased growth, migration/invasion, compromised expression of ER? target genes, and markedly altered gene expression patterns.

SUBMITTER: Huderson BP

PROVIDER: S-EPMC3423624 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Stable inhibition of specific estrogen receptor α (ERα) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells.

Huderson B P BP Duplessis T T TT Williams C C CC Seger H C HC Marsden C G CG Pouey K J KJ Hill S M SM Rowan B G BG

Endocrinology 20120625 9

Elevated phosphorylation of estrogen receptor α (ERα) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ERα signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ERα signaling, resulting in aggressive ERα-independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ERα-specific short hairp ...[more]

PMID: 22733972

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Project description:PurposeCyclase-associated protein 1 (CAP1) is a ubiquitous protein which regulates actin dynamics. Previous studies have shown that S308 and S310 are the two major phosphorylated sites in human CAP1. In the present study, we aimed to investigate the role of CAP1 phosphorylation in lung cancer.MethodsMassive bioinformatics analysis was applied to determine CAP1's role in different cancers and especially in lung cancer. Lung cancer patients' serum and tissue were collected and analyzed in consideration of clinical background. CAP1 shRNA-lentivirus and siRNA were applied to CAP1 gene knockdown, and plasmids were constructed for CAP1 phosphorylation and de-phosphorylation. Microarray analysis was used for CAP1-associated difference analysis. Both in vitro and in vivo experiments were performed to investigate the roles of CAP1 phosphorylation and de-phosphorylation in lung cancer A549 cells.ResultsCAP1 is a kind of cancer-related protein. Its mRNA was overexpressed in most types of cancer tissues when compared with normal tissues. CAP1 high expression correlated with poor prognosis. Our results showed that serum CAP1 protein concentrations were significantly upregulated in non-small cell lung cancer (NSCLC) patients when compared with the healthy control group, higher serum CAP1 protein concentration correlated with shorter overall survival (OS) in NSCLC patients, and higher pCAP1 and CAP1 protein level were observed in lung cancer patients' tumor tissue compared with adjacent normal tissue. Knockdown CAP1 in A549 cells can inhibit proliferation and migration, and the effect is validated in H1975 cells. It can also lead to an increase ratio of F-actin/G-actin. In addition, phosphorylated S308 and S310 in CAP1 promoted lung cancer cell proliferation, migration, and metastasis both in vitro and in vivo. When de-phosphorylated, these two sites in CAP1 showed the opposite effect. Phosphorylation of CAP1 can promote epithelial-mesenchymal transition (EMT).ConclusionThese findings indicated that CAP1 phosphorylation can promote lung cancer proliferation, migration, and invasion. Phosphorylation sites of CAP1 might be a novel target for lung cancer treatment.

Dataset Information

Stable inhibition of specific estrogen receptor ? (ER?) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells.

Publications

Stable inhibition of specific estrogen receptor α (ERα) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells.

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