PMID:20124477

Citation	Tran, TH, Utama, FE, Lin, J, Yang, N, Sjolund, AB, Ryder, A, Johnson, KJ, Neilson, LM, Liu, C, Brill, KL, Rosenberg, AL, Witkiewicz, AK and Rui, H (2010) Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism. Cancer Res. 70:1711-21
Abstract	BCL6 is a transcriptional repressor that recognizes DNA target sequences similar to those recognized by signal transducer and activator of transcriptions 5 (Stat5). BCL6 disrupts differentiation of breast epithelia, is downregulated during lactation, and is upregulated in poorly differentiated breast cancer. In contrast, Stat5a mediates prolactin-induced differentiation of mammary epithelia, and loss of Stat5 signaling in human breast cancer is associated with undifferentiated histology and poor prognosis. Here, we identify the mammary cell growth factor prolactin as a potent suppressor of BCL6 protein expression in human breast cancer through a mechanism that requires Stat5a, but not prolactin-activated Stat5b, MEK-ERK, or PI3K-AKT pathways. Prolactin rapidly suppressed BCL6 mRNA in T47D, MCF7, ZR75.1, and SKBr3 breast cancer cell lines, followed by prolonged reduction of BCL6 protein levels within 3 hours. Prolactin suppression of BCL6 was enhanced by overexpression of Stat5a but not Stat5b, was mimicked by constitutively active Stat5a, but did not require the transactivation domain of Stat5a. Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes. Prolactin suppression of BCL6 was extended to xenotransplant tumors in nude mice in vivo and to freshly isolated human breast cancer explants ex vivo. Quantitative immunohistochemistry revealed elevated BCL6 in high-grade and metastatic breast cancer compared with ductal carcinoma in situ and nonmalignant breast, and cellular BCL6 protein levels correlated negatively with nuclear Stat5a (r = -0.52; P < 0.001) but not with Stat5b. Loss of prolactin-Stat5a signaling and concomitant upregulation of BCL6 may represent a regulatory switch facilitating undifferentiated histology and poor prognosis of breast cancer.
Links	PubMed PMC2822876 Online version:10.1158/0008-5472.CAN-09-2314
Keywords	Animals; Breast Neoplasms/diagnosis; Breast Neoplasms/genetics; Breast Neoplasms/pathology; Carcinoma/diagnosis; Carcinoma/genetics; Carcinoma/pathology; Cell Line, Tumor; Cells, Cultured; DNA-Binding Proteins/genetics; Down-Regulation/drug effects; Female; Gene Expression Regulation, Neoplastic/drug effects; Humans; Mice; Mice, Nude; Prognosis; Prolactin/pharmacology; Prolactin/physiology; STAT5 Transcription Factor/genetics; STAT5 Transcription Factor/physiology; Signal Transduction/drug effects; Signal Transduction/genetics; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/physiology; Xenograft Model Antitumor Assays
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status

References

See Help:References for how to manage references in GONUTS.