Our long-term objective is to elucidate how growth-regulatory signaling networks regulate normal growth and neoplastic transformation of mammary epithelial cells. Our studies focus on Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). JAKs and STATs are important intermediaries in """"""""the lines of fire"""""""" of various growth factor receptors that are implicated in breast cancer. A primary objective of our current research is to examine how JAK/STAT signaling is altered in breast cancer models that initiate tumorigenesis through hyperstimulation of growth factor receptors (i.e.prolactin receptor and ErbB2) that utilize Jak2 and/or StatS and Stat3 as signal transducers. We developed a unique model system that enables us to genetically modify JAK/STAT signaling both prior to growth factor-mediated neoplastic transformation and during particular stages of the progressing disease. We hypothesize that inhibiting the growth factor- mediated activation of STATs through inactivation of Jak2 will reduce the onset of neoplastic transformation in these tumor models. This will suggest that targeting Jak2 is a relevant strategy for breast cancer prevention in individuals with hyperprolactinemia or patients that are at risk of developing pregnancy-associated breast cancers that are frequently ErbB2-positive. In contrast, the ablation of Jak2/Stat5/3 signaling in neoplastic cells (therapeutic intervention) might result in a different outcome depending on the type of growth factor- initiated transformation, and,more importantly, the stage of the progressing lesion.
The specific aims of this proposal are to determine a hierarchy of diverse signaling transducers (aim 1) that serve as biomarkers for the analysis of prolactin and ErbB2 overexpressing cancer cells. Furthermore, the proposed studies will address mechanistic aspects about the autocrine role of prolactin in breast cancer (aim2) as well as the suggested Jak2-mediated receptor crosstalk between the prolactin receptor and ErbB2 (aim 3). The results of these analyses might, discriminate subtypes of breast cancer, in which targeting Jak2 is therapeutically relevant. Furthermore, they might reveal whether a combinatorial therapy of pan-ErbB tyrosine kinase inhibitors and Jak2 inhibitors would be beneficial for the treatment of ErbB2-positive breast cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-U (90))
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Spalholz, Barbara A
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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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