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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085492-14
Application #
8610248
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2000-05-20
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$407,521
Indirect Cost
$114,292
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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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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