Breast cancer is a leading cause of death among women. Malignant breast tumors that are not cured by initial surgery typically respond poorly to traditional chemotherapy and further antiestrogen therapy. New therapeutic strategies that will inhibit growth and suppress progression of breast cancer cells need to be identified. This goal might be achieved through targeting of signaling pathways used by the most prominent peptide hormones that regulate breast cancer growth and differentiation. Based on novel preliminary data that extend the work supported by this grant, we provide compelling rationale for investigating the growth-regulatory role of the prolactin-activated Jak2 tyrosine kinase/Stat5 transcription factor pathway in normal and malignant human breast epithelial cells. Importantly, we have discovered loss of Stat5 activation during progression from normal to primary cancer and to metastatic disease. We have also discovered a novel prolatin-activated Jak1-Stat3 signaling pathway that is Jak2-independent, and appears to require the interleukin-6 signal transducer, gp130. We will use specialized molecular tools and technologies to test the following two central hypotheses: a) Prolactin inhibits growth of normal and malignant human breast epithelial cells through activation of the Jak2-Stat5 signaling pathway. b) Prolactin activates an alternative, breast cancer-specific Jak1-Stat3 pathway by a mechanism that requires the interleukin-6 signal transducer, gpl30. We are well qualified to successfully undertake the proposcd studies. We expect to establish the importance of the Jak2-Stat5 pathway in growth-suppression of untransformed and malignant breast epithelial cells, and to identify the mechanism by of aberrant prolactin activation of the Jak 1-Stat3 pathway in breast cancer cells. The research is significant and important because it will provide novel insight into the biological role and mechanisms of prolactin signal transduction in breast cancer. More effective therapeutic strategies for breast cancer could be a result.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052013-06
Application #
6665384
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Blondel, Olivier
Project Start
1998-09-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$232,340
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Utama, Fransiscus E; Tran, Thai H; Ryder, Amy et al. (2009) Insensitivity of human prolactin receptors to nonhuman prolactins: relevance for experimental modeling of prolactin receptor-expressing human cells. Endocrinology 150:1782-90
Wagner, Kay-Uwe; Rui, Hallgeir (2008) Jak2/Stat5 signaling in mammogenesis, breast cancer initiation and progression. J Mammary Gland Biol Neoplasia 13:93-103
Neilson, Lynn M; Zhu, Jianquong; Xie, Jianwu et al. (2007) Coactivation of janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer: recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways. Mol Endocrinol 21:2218-32
LeBaron, M J; Ahonen, T J; Nevalainen, M T et al. (2007) In vivo response-based identification of direct hormone target cell populations using high-density tissue arrays. Endocrinology 148:989-1008
Utama, F E; LeBaron, M J; Neilson, L M et al. (2006) Human prolactin receptors are insensitive to mouse prolactin: implications for xenotransplant modeling of human breast cancer in mice. J Endocrinol 188:589-601
LeBaron, Matthew J; Xie, Jianwu; Rui, Hallgeir (2005) Evaluation of genome-wide chromatin library of Stat5 binding sites in human breast cancer. Mol Cancer 4:6
LeBaron, Matthew J; Crismon, Heidi R; Utama, Fransiscus E et al. (2005) Ultrahigh density microarrays of solid samples. Nat Methods 2:511-3
Rui, Hallgeir; LeBaron, Matthew J (2005) Creating tissue microarrays by cutting-edge matrix assembly. Expert Rev Med Devices 2:673-80
Sultan, Ahmed S; Xie, Jianwu; LeBaron, Matthew J et al. (2005) Stat5 promotes homotypic adhesion and inhibits invasive characteristics of human breast cancer cells. Oncogene 24:746-60
Krempler, Andrea; Qi, Yongyue; Triplett, Aleata A et al. (2004) Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40:52-7

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