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Transcriptional Activation of Signal Transducer and Activator of Transcription (STAT) 3 and STAT5B Partially Mediate Homeobox A1-Stimulated Oncogenic Transformation of the Immortalized Human Mammary Epithelial Cell

The Liggins Institute and National Research Centre for Growth and Development (K.M.M., J.K.P., N.K., P.D.G., B.S.E., P.E.L.), and Department of Molecular Medicine and Pathology, Faculty of Medical Health Sciences (P.E.L.) University of Auckland, Auckland 1142, New Zealand; and Departments of Molecular Biology and Surgery (K.K.), University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan

Address all correspondence and requests for reprints to: Peter E. Lobie, The Liggins Institute, University of Auckland, 2–6 Park Avenue, Private Bag 92019, Auckland 1142, New Zealand. E-mail: p.lobie{at}auckland.ac.nz.

We have previously demonstrated that the p44/42 MAPK pathway is one pathway involved in homeobox (HOX) A1-stimulated oncogenesis. However, inhibition of MAPK kinase 1 does not completely prevent HOXA1-stimulated oncogenic transformation, suggesting the involvement of additional signal transduction pathways. Here, we report that forced expression of HOXA1 in immortalized human mammary epithelial cells significantly increased levels of signal transducer and activator of transcription (STAT) 3, 5A, and 5B mRNA by transcriptional up-regulation. The protein levels of STAT3 and 5B, but not STAT5A, and protein phosphorylation levels of STAT3 and 5B were significantly increased by forced expression of HOXA1. Forced expression of STAT3 or STAT5B was sufficient to transform oncogenically an immortalized human mammary epithelial cell line. Accordingly, inhibition of STAT3 or STAT5B activity with dominant negative STAT3 or STAT5B abrogated the ability of HOXA1 to stimulate cell proliferation, survival, oncogenic transformation, and generation of large disorganized multiacinar structures in three-dimensional culture. These results suggest that HOXA1 partially mediates oncogenic transformation of the immortalized human mammary epithelial cell through modulation of the STAT3 and STAT5B pathways.