Each year, more than one million new cases of breast cancer are diagnosed worldwide, and an estimated 370,000 women die from breast cancer. The vast majority of fatal breast cancer cases involve metastatic spread of the primary tumor, but the metastatic process remains a complex and poorly understood process. Our long-range goal is to identify the molecular mechanisms of breast cancer progression from solitary tumor to metastasis. Based on our extensive molecular analysis of clinical human breast cancer specimens and a series of experimental breast cancer models, we now propose to test the following central hypothesis: Loss of activation of transcription factor Stat5 is a cancer progression event that favors epithelial-to-mesenchymal dedifferentiation, invasiveness, and increased metastatic potential of breast cancer cells. To accomplish the objectives of this application, we will pursue three specific aims:
Aim #1 : Analyze 1,300 human breast cancer specimens to establish the relationship between levels of active Stat5 and measures of tumor cell invasiveness.
Aim #2 : Establish whether Stat5 stimulates human breast cancer cell differentiation and adhesion, and suppresses tumor cell invasion, in vitro and in vivo.
Aim #3 : Determine the effect of Stat5 activation on invasion and metastasis of mouse breast cancer models in vivo. Our expectations are that by the end of the proposed project period, we will have established whether Stat5 activation status in breast cancer is a useful clinical predictor of disease progression and clinical outcome in lymph node-negative breast cancer. This is important because active Stat5 may serve as a simple immunohistochemical marker to identify node-negative breast cancer patients with excellent prognosis, permitting more individualized treatment, including selection of antiestrogen therapy. The results of this work could lead to new preventative and therapeutic strategies for primary and metastatic breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA101841-01A1
Application #
6776600
Study Section
Special Emphasis Panel (ZRG1-CBSS (01))
Program Officer
Lively, Tracy (LUGO)
Project Start
2004-06-23
Project End
2009-05-31
Budget Start
2004-06-23
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$234,702
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
Sato, T; Tran, T H; Peck, A R et al. (2014) Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene 33:2215-24
Sato, Takahiro; Tran, Thai H; Peck, Amy R et al. (2013) Global profiling of prolactin-modulated transcripts in breast cancer in vivo. Mol Cancer 12:59
Yang, Ning; Liu, Chengbao; Peck, Amy R et al. (2013) Prolactin-Stat5 signaling in breast cancer is potently disrupted by acidosis within the tumor microenvironment. Breast Cancer Res 15:R73
Peck, Amy R; Witkiewicz, Agnieszka K; Liu, Chengbao et al. (2012) Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. Breast Cancer Res 14:R130
Peck, Amy R; Witkiewicz, Agnieszka K; Liu, Chengbao et al. (2011) Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin Oncol 29:2448-58
Sato, Takahiro; Neilson, Lynn Moretti; Peck, Amy R et al. (2011) Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res 1:347-55
Tran, Thai Hong; Lin, Justin; Sjolund, Ashley Brooke et al. (2010) Protocol for constructing tissue arrays by cutting edge matrix assembly. Methods Mol Biol 664:45-52
Johnson, Kevin J; Peck, Amy R; Liu, Chengbao et al. (2010) PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol 177:2971-83
Tran, Thai H; Utama, Fransiscus E; Lin, Justin et al. (2010) Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism. Cancer Res 70:1711-21
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

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