Our long-term objective is to elucidate how growth-regulatory signaling networks control the multiplication, differentiation, and survival of normal and neoplastic mammary epithelial cells. Our current studies focus on the biologically relevant functions of Jak2 and Stat5 which are important intermediaries in the lines of fire of various growth factor receptors that are implicated in breast tumorigenesis. We recently demonstrated that Jak2 and active Stat5 are essential for ErbB2- and prolactin-induced mammary carcinogenesis. In addition, we discovered that Stat5 enhances the expression of Akt1 through transcriptional activation of this gene from a novel, mammary-specific promoter. A gain-of-function of Stat5 in vivo is sufficient to upregulate the expression and activation of Akt1, which subsequently mediates a sustained survival of mammary epithelial cells. Hence, like PI3K/Akt1 signaling, an active Jak2/Stat5 cascade facilitates two important hallmarks of cancer, i.e. evasion from apoptosis and self-sufficiency in growth signals. Since mutations in PI3K and loss-of-function of PTEN are common molecular aberrations observed in sporadic as well as hereditary forms of breast cancer (e.g., Cowden Syndrome), the primary goal of this project is to examine whether the association of Jak/Stat signaling and the PI3K/Akt1 pathway plays an important role in breast cancer. Our general hypothesis is that the Jak2/Stat5 signaling cascade is a potent modifier for the onset of neoplastic transformation that is caused by a hyperactivation of the PI3K/Akt1 pathway in conjunction with a mutation in the PTEN tumor suppressor. In addition, we anticipate that Akt1 is a main downstream effector that executes oncogenic properties of mutant PTEN and active Stat5. To experimentally address this hypothesis, we will assess in the first specific aim whether alterations in Jak2/Stat5 signaling affect the onset of PTEN-associated mammary cancer. Akt1 acts downstream of Stat5 and PTEN, and we will therefore determine in the second specific aim whether Akt1 is a suitable target for the prevention and treatment of Stat5-induced and PTEN-associated mammary cancer. Since we have found that the mammary-specific Akt1 transcripts are conserved between mice and humans, we will assess in the third specific aim whether targeting these unique mRNAs has an effect on breast cancer cell growth and survival. Collectively, the results of this project will give insight into the molecular mechanisms by which Jak2 and Stat5 act as modifiers for the onset of sporadic as well as hereditary forms of breast cancer that lack functional PTEN. The outcome of this study might provide evidence for extending the use of Jak2 inhibitors as a novel approach toward breast cancer prevention, and this project will establish whether Akt1 is a therapeutic target for PTEN-associated breast cancers. Finally, we will assess a new strategy to modulate the expression of Akt1 on the transcriptional level specifically in the mammary epithelium.

Public Health Relevance

Growth factors and their downstream mediators play an important role in the etiology of breast cancer. The objective of this project is to elucidate how Jak2/Stat5 signaling regulates the activity of the PI3 kinase/Akt1 pathway and contributes to mammary tumorigenesis. The results of this project will provide insight into the molecular mechanisms by which Jak2, Stat5, and Akt1 act as important intermediaries in growth factor receptor signaling networks that are implicated in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA117930-06A1
Application #
8234382
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R,
Project Start
2006-02-04
Project End
2017-03-31
Budget Start
2012-05-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$255,944
Indirect Cost
$83,591
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Schmidt, Jeffrey W; Wehde, Barbara L; Sakamoto, Kazuhito et al. (2014) Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells. BMC Cancer 14:195
Lin, Wan-Chi; Rajbhandari, Nirakar; Wagner, Kay-Uwe (2014) Cancer cell dormancy in novel mouse models for reversible pancreatic cancer: a lingering challenge in the development of targeted therapies. Cancer Res 74:2138-43
Schmidt, Jeffrey W; Wehde, Barbara L; Sakamoto, Kazuhito et al. (2014) Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis. Mol Cell Biol 34:1363-77
Grisouard, Jean; Hao-Shen, Hui; Dirnhofer, Stephan et al. (2014) Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia. Haematologica 99:e52-4
Lin, Wan-chi; Schmidt, Jeffrey W; Creamer, Bradley A et al. (2013) Gain-of-function of Stat5 leads to excessive granulopoiesis and lethal extravasation of granulocytes to the lung. PLoS One 8:e60902
Park, Sung O; Wamsley, Heather L; Bae, Kyungmi et al. (2013) Conditional deletion of Jak2 reveals an essential role in hematopoiesis throughout mouse ontogeny: implications for Jak2 inhibition in humans. PLoS One 8:e59675
Zhang, Qian; Sakamoto, Kazuhito; Wagner, Kay-Uwe (2013) D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells. Mol Cell Endocrinol :
Rucker 3rd, Edmund B; Hale, Amber N; Durtschi, David C et al. (2011) Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein bax. Genesis 49:24-35
Zhang, Qian; Sakamoto, Kazuhito; Liu, Chengbao et al. (2011) Cyclin D3 compensates for the loss of cyclin D1 during ErbB2-induced mammary tumor initiation and progression. Cancer Res 71:7513-24
Sos, Brandon C; Harris, Charles; Nordstrom, Sarah M et al. (2011) Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. J Clin Invest 121:1412-23

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