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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Yassin, Rihab R,
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University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Rädler, Patrick D; Wehde, Barbara L; Wagner, Kay-Uwe (2017) Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells. Mol Cell Endocrinol 451:31-39
Sakamoto, Kazuhito; Wehde, Barbara L; Yoo, Kyung Hyun et al. (2016) Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling. Mol Cell Biol 36:1673-90
Sánchez-Bailón, María Pilar; Calcabrini, Annarica; Mayoral-Varo, Víctor et al. (2015) Cyr61 as mediator of Src signaling in triple negative breast cancer cells. Oncotarget 6:13520-38
Gan, Xiaohong T; Rajapurohitam, Venkatesh; Xue, Jenny et al. (2015) Myocardial Hypertrophic Remodeling and Impaired Left Ventricular Function in Mice with a Cardiac-Specific Deletion of Janus Kinase 2. Am J Pathol 185:3202-10
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
Zhang, Qian; Sakamoto, Kazuhito; Wagner, Kay-Uwe (2014) D-type Cyclins are important downstream effectors of cytokine signaling that regulate the proliferation of normal and neoplastic mammary epithelial cells. Mol Cell Endocrinol 382:583-592
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
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; 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

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