This laboratory investigates the genes and signaling pathways, which guide mammary development during puberty, pregnancy, lactation, involution and neoplasia. Both systemic endocrine hormones and local growth regulators control distinct phases of mammopoiesis. Gene deletion and tissue transplantation approaches were used to investigate the prolactin (Prl) signaling pathway and the Brca1 gene during normal and neoplastic development. After binding to its receptor, Prl activates the Jak/Stat pathway and induces a developmental program. We had previously deleted the Stat5a gene from the mouse genome and demonstrated that Prl signaling through the Jak2/Stat5 pathway is essential for the proliferation and functional differentiation of lobulo-alveolar structures during pregnancy. Surprisingly, Stat5b, which is 96% conserved with Stat5a, is not required for mammary development and function. However, we could demonstrate that in the absence of Stat5a, extensive hormonal stimulation leads to the activation of Stat5b, which can partially compensate for the absence of Stat5a. It had been suggested that the Jak2/Stat5a pathway contributes to the establishment of neoplasias. To test this hypothesis we analyzed transgenic mice expressing TGF-alpha in mammary tissue in the presence and absence of an intact Stat5a pathway. Mice that express transgenic TGF-alpha in mammary tissue develop mammary hyperplasias and tumors. In the absence of Stat5a, the development of hyperplasias is delayed. Additional experiments demonstrated that Stat5a is a survival factor in mammary epithelial cells.We recently developed the Cre-loxP recombination system to delete genes from specific cell types in the mouse. Specifically we generated mice that express the Cre enzyme specifically in mammary cells (WAP-Cre mice) and in a wider tissue setting (MMTV-Cre mice). In collaboration with Dr. C. Deng (NIDDK) we used these mice to delete the Brca1 gene specifically from mammary tissue during pregnancy. These experiments demonstrated that Brca1 is required for normal mammary development, and that the absence of Brca1 leads to mammary tumors that recapitulate human breast cancer. Current efforts focus on the analysis of the cell survival factors bcl-x and Jak2 in mammary epithelial cells and their role in development and tumorigenesis.In an attempt to identify genes that are regulated (directly or indirectly by the transcription factor Stat5a, we performed subtractive gene cloning. As part of this approach we identified a genetic locus on chromosome 11 that is under control of an MMTV provirus. We discovered that this MMTV provirus activates the neighboring genomic region and as part of a large transcripts picks up hitchhiking exons. This finding demonstrates that proviruses can activate genomic sequences and engage in alternative splicing. - mammary development tumors prolactin Stat C/EBPbeta gene deletion transgenic mice Cre-loxP recombination mammary transplants

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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U.S. National Inst Diabetes/Digst/Kidney
United States
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Hosui, Atsushi; Kimura, Akiko; Yamaji, Daisuke et al. (2009) Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation. J Exp Med 206:819-31
Klover, Peter; Chen, Weiping; Zhu, Bing-Mei et al. (2009) Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor. FASEB J 23:3140-8
Hikita, Hayato; Takehara, Tetsuo; Kodama, Takahiro et al. (2009) BH3-only protein bid participates in the Bcl-2 network in healthy liver cells. Hepatology 50:1972-80
Hager, Jeffrey H; Ulanet, Danielle B; Hennighausen, Lothar et al. (2009) Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer. PLoS One 4:e4455
Zhu, Bing-Mei; Ishida, Yuko; Robinson, Gertraud W et al. (2008) SOCS3 negatively regulates the gp130-STAT3 pathway in mouse skin wound healing. J Invest Dermatol 128:1821-9
Byts, N; Samoylenko, A; Fasshauer, T et al. (2008) Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ 15:783-92
Oshima, Yasushi; Akiyama, Toru; Hikita, Atsuhiko et al. (2008) Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis. J Biol Chem 283:26499-508
Hennighausen, Lothar; Robinson, Gertraud W (2008) Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev 22:711-21
Lee, Ji-Yeon; Gavrilova, Oksana; Davani, Behrous et al. (2007) The transcription factors Stat5a/b are not required for islet development but modulate pancreatic beta-cell physiology upon aging. Biochim Biophys Acta 1773:1455-61
Cui, Yongzhi; Hosui, Atsushi; Sun, Rui et al. (2007) Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology 46:504-13

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