Naturally occurring dominant-negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells

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Abstract
Signal transducer and activator of transcription (Stat) 5 regulates growth, differentiation, and survival of mammary and hematopoietic cells. The role of Stat5 in breast cancer has not been established, although Stat5 is critical for some hematopoietic malignancies. We detected for the first time that Stat5b is constitutively activated in human breast cancer cell lines, and analysed the role of Stat5 in estrogen receptor(ER)-positive breast cancer cell lines using dominant-negative variants of Stat5. Two distinct carboxyl-truncated Stat5a derivatives were generated. Stat5aΔ740 corresponded to a naturally occurring alternative splice variant, and Stat5aΔ713 was analogous to an 80 kDa Stat5a product of a nuclear protease. Stat5aΔ740 and Stat5aΔ713 displayed comparable dominant-negative properties and suppressed transcriptional activity of wild-type Stat5a and Stat5b equally well. Cotransfection experiments revealed that Stat5aΔ740 completely blocked transcriptional activity of endogenous estrogen receptor in T47D and MCF7 cells, and of both ERα and ERβ in COS-7 cells. Stat5aΔ740 was selected for adenoviral delivery, and high-efficiency expression of tyrosine phosphorylated Stat5aΔ740 was achieved in infected cells. Adenoviral-mediated Stat5aΔ740 induced apoptosis in T47D cells but not in caspase-3-negative MCF7 cells. The present study indicates that overexpression of a dominant-negative variant of Stat5 suppresses ER transcriptional activity and induces apoptosis in estrogen-responsive breast cancer tissue culture cells.