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Estrogen-Mediated Suppression of the Gene Encoding Protein Tyrosine Phosphatase PTPRO in Human Breast Cancer: Mechanism and Role in Tamoxifen Sensitivity

Department of Molecular and Cellular Biochemistry (S.M., K.G., J.D., S.T.J.), Department of Internal Medicine (B.R., C.L.S., S.T.J.), College of Medicine, and the Comprehensive Cancer Center (B.R., S.M., S.R., K.G., H.K., J.D., C.L.S., T.M., S.T.J.), Ohio State University, Columbus, Ohio 43210; and Department of Pathology (M.Y.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Samson T. Jacob, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio. E-mail: samson.jacob@osumc.edu; or Tasneem Motiwala, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio. E-mail: tasneem.motiwala{at}osumc.edu.

We have previously demonstrated the tumor suppressor characteristics of protein tyrosine phosphatase receptor-type O (PTPRO) in leukemia and lung cancer, including its suppression by promoter methylation. Here, we show tumor-specific methylation of the PTPRO CpG island in primary human breast cancer. PTPRO expression was significantly reduced in established breast cancer cell lines MCF-7 and MDA-MB-231 due to promoter methylation compared with its expression in normal human mammary epithelial cells (48R and 184). Further, the silenced gene could be demethylated and reactivated in MCF-7 and MDA-MB-231 cells upon treatment with 5-Azacytidine, a DNA hypomethylating agent. Because PTPRO promoter harbors estrogen-responsive elements and 17β-estradiol (E2) plays a role in breast carcinogenesis, we examined the effect of E2 and its antagonist tamoxifen on PTPRO expression in human mammary epithelial cells and PTPRO-expressing breast cancer cell line Hs578t. Treatment with E2 significantly curtailed PTPRO expression in 48R and Hs578t cells, which was facilitated by ectopic expression of estrogen receptor (ER)β but not ER. On the contrary, treatment with tamoxifen increased PTPRO expression. Further, knockdown of ERβ by small interfering RNA abolished these effects of E2 and tamoxifen. Chromatin immunoprecipitation assay showed association of c-Fos and c-Jun with PTPRO promoter in untreated cells, which was augmented by tamoxifen-mediated recruitment of ERβ to the promoter. Estradiol treatment resulted in dissociation of c-Fos and c-Jun from the promoter. Ectopic expression of PTPRO in the nonexpressing MCF-7 cells sensitized them to growth-suppressive effects of tamoxifen. These data suggest that estrogen-mediated suppression of PTPRO is probably one of the early events in estrogen-induced tumorigenesis and that expression of PTPRO could facilitate endocrine therapy of breast cancer.

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