Abstract
The tumor suppressor gene p53 is frequently mutated in human breast cancer and is a marker for poor prognosis and resistance to chemotherapy. Transplantation of p53 null mouse mammary epithelium into syngeneic wild-type mice leads to normal mammary gland development followed by spontaneous mammary tumors that recapitulate many of the phenotypic, molecular and genetic features of human breast cancer. Transient exposure of p53 null mice to the anti-estrogen, tamoxifen leads to sustained and robust protection against tumor development. However the mechanism underlying this anti-tumor activity remains poorly understood. Here we demonstrate that transient exposure to tamoxifen leads to a reduction in mammary ductal side-branching and epithelial cell proliferation after tamoxifen withdrawal. Global gene expression analysis showed that transient tamoxifen exposure leads to persistent changes in the expression of a subset of estrogen regulated gene signatures in mammary epithelial cells (MECs). Among these was the protein tyrosine phosphatase, non-receptor type 5 (Ptpn5). We show that Ptpn5 is a novel tamoxifen regulated target gene which is upregulated in MECs after transient tamoxifen exposure and displays tumor suppressor activity in human breast cancer cells. Further, PTPN5 expression is strongly associated with good clinical outcome in tamoxifen treated human breast cancer patients suggesting that PTPN5 may represent a novel biomarker of tamoxifen response in human breast cancer.
Highlights
Breast cancer (BC) comprises a heterogeneous group of diseases that can be discriminated at the molecular level into approximately six distinguishable subtypes based on genome-wide transcription profiling [1,2,3]
We disclose the intrinsic changes in the Estrogen receptor α (ERα) responsive genes that are associated with tamoxifendependent tumor protection and we address the functional contribution of a novel tamoxifen regulated target gene, the protein tyrosine phosphatase, PTPN5 to tumor suppression in a xenograft model of p53 mutant human BC
We further demonstrated that Ptpn5 is a direct target of ERα whose expression is acutely repressed by E2 and strongly upregulated by tamoxifen in the WT mammary gland (Fig 5A) indicating that Ptpn5 is induced by TAM in p53 null mammary gland and in WT mammary gland
Summary
Breast cancer (BC) comprises a heterogeneous group of diseases that can be discriminated at the molecular level into approximately six distinguishable subtypes based on genome-wide transcription profiling [1,2,3]. Endocrine therapy using aromatase inhibitors (AIs) to block estrogen production or antiestrogen selective estrogen receptor modulators (SERMS) remain the most widely used and most effective treatment for breast cancers in women who have tumors positive for ERα [9]. Both SERMS and AIs have been shown to confer substantial protection (>50%) against ER+ breast cancer development leading to FDA approval of tamoxifen and raloxifene to reduce BC risk in women at high risk of BC development [10,11,12,13]
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