The TGF-? pathway potently regulates tumor initiation, progression and metastasis. Work supported by this grant over the current funding period has shown that impairment of TGF-? signaling, when combined with oncogene activation or tumor suppressor gene attenuation, accelerates the development of carcinomas and enhances tumor progression, including metastasis. Mechanistic studies utilizing the mammary gland models, MMTV-PyMT and MMTV- c-neu, have shown that a major mechanism whereby loss or attenuation of TGF-? signaling accelerates tumor progression is increased secretion of cytokines and chemokines by . In the mouse models increased chemokine expression resulted in recruitment of myeloid/immune cells with resultant enhancement of invasion and metastasis. We now have another model in which a single genetic alteration results in a 4-5 fold increase in lung metastases with different mechanisms. The following three hypotheses will be tested in the proposed studies: 1) A major function of TGF-? signaling is the suppression of chemokine and cytokine expression, and attenuation or loss of TGF-? signaling in carcinoma cells leads to increased secretion of different chemokines and cytokines that play different roles in enhancing metastasis. 2) A mechanism of myeloid/immune cell enhancement of tumor invasion and metastasis is through secretion of TGF-?, which induces lysyl oxidase (LOX) that cross-links collagen increasing matrix stiffness and enhancing invasion. 3) The gene expression signature and patterns of expression of selected chemokines and cytokines in tissue microarrays (TMA) of impaired TGF-? signaling in our models will predict for worse outcome when applied to publically available human breast cancer datasets. The following specific aims are proposed to test these hypotheses: 1) Determine the mechanism of enhancement of c-neu-induced tumor metastasis by a dominant negative type II TGF-? receptor (DNIIR);2) determine the mechanism(s) of myeloid/immune cell promotion of tumor invasion and metastasis in the PyMT model with conditional knockout of the type II TGF-? receptor and in the c-neu/DNIIR model;and 3) Determine whether mechanisms identified in the mouse models are applicable to human breast cancer.

Public Health Relevance

TGF-? signaling is a major tumor suppressor pathway in human carcinomas, but in later stages of tumor progression, TGF-? signaling promotes tumor progression. As systemic inhibitors of TGF-? signaling are in clinical trials in humans with cancer, it is important to delineate mechanisms of both suppression and promotion of tumors by TGF-?. We have excellent mouse models and plans for such mechanistic studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Mohla, Suresh
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Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
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Pickup, Michael W; Hover, Laura D; Polikowsky, Eleanor R et al. (2015) BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Mol Oncol 9:179-91
Ryzhov, Sergey V; Pickup, Michael W; Chytil, Anna et al. (2014) Role of TGF-? signaling in generation of CD39+CD73+ myeloid cells in tumors. J Immunol 193:3155-64
Rubashkin, Matthew G; Cassereau, Luke; Bainer, Russell et al. (2014) Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Res 74:4597-611
Rubashkin, Matthew G; Ou, Guanqing; Weaver, Valerie M (2014) Deconstructing signaling in three dimensions. Biochemistry 53:2078-90
Jovanovi?, Bojana; Beeler, J Scott; Pickup, Michael W et al. (2014) Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer. Breast Cancer Res 16:R69
Rahman, Mohummad Aminur; Kristiansen, Per E; Veiseth, Silje V et al. (2014) The arabidopsis histone methyltransferase SUVR4 binds ubiquitin via a domain with a four-helix bundle structure. Biochemistry 53:2091-100
Mouw, Janna K; Yui, Yoshihiro; Damiano, Laura et al. (2014) Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med 20:360-7
Damiano, L; Stewart, K M; Cohet, N et al. (2014) Oncogenic targeting of BRM drives malignancy through C/EBP*-dependent induction of *5 integrin. Oncogene 33:2441-53
Owens, Philip; Polikowsky, Hannah; Pickup, Michael W et al. (2013) Bone Morphogenetic Proteins stimulate mammary fibroblasts to promote mammary carcinoma cell invasion. PLoS One 8:e67533
Pickup, Michael; Novitskiy, Sergey; Moses, Harold L (2013) The roles of TGF* in the tumour microenvironment. Nat Rev Cancer 13:788-99

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