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The VICC.ORG Investigator Directory

Carlos L. Arteaga, M.D.

Donna S. Hall Chair in Breast Cancer
Professor of Medicine and Cancer Biology
Associate Director of Clinical Research
Director, VICC Breast Cancer Program
VICC Member
Medical Oncologist

Patient Contact Information:

1-800-811-8480

Nashville Veterans Affairs Medical Center
1310 24th Ave. South
Nashville , TN 37212-2637
Phone: 615-327-4751
Fax: 615-321-6350

Healthcare Provider Contact Information:

Vanderbilt-Ingram Cancer Center
683 Preston Building
Nashville, TN 37232-6838
615-936-3524

Research Specialty:

Oncogene signaling in mammary development/transformation and breast cancer progression

Research Description:

My laboratory is funded to study signaling by receptors of the EGF (erbB) family as well as the TGFbeta receptor serine threonine kinases in the phenotype of breast tumor cells. Our long term goal is to use this information for [1] the better characterization of clinical breast cancer syndromes, and [2] develop and test molecular-based rational treatment concepts against human breast carcinoma.

Recent data from our laboratory and others indicate that overexpression of EGFR (HER1, erbB1) and/or HER2/neu (erbB2) tyrosine kinases in tumor cells upregulates a number of cell cycle and anti-apoptosis pathways leading to subversion of cell cycle checkpoints and enhanced cancer cell survival and metastatic potential. In turn, inhibition of these kinases with pharmacological or genetic means, reverses the aberrant signaling in receptor-overexpressing cells and, in some cases, results in growth arrest and/or tumor cell death. We focus on 1) the mechanisms by which these receptors transform mammary epithelial cells, 2) the signaling mechanisms that need to be inhibited in order for anti-receptor strategies to be effective, and 3) the mechanisms of tumor cell resistance to these approaches. For this purpose we use conventional molecular and biochemical methods, proteomic approaches, primary tumors and cell lines from patients with breast cancer, and transgenic mouse models of mammary development and neoplasia.

More recently, activating mutations of the EGFR and HER2 have been reported in human carcinomas that respond exquisitely to erbB tyrosine kinase inhibitors. The molecular mechanisms by which these mutants confer a gain-of-function are an important addition to our research portfolio. Moreover, aberrant EGFR/HER2 signaling has been associated with antiestrogen resistance in breast cancer. The molecular mechanisms by which erbB receptor signaling modifies the estrogen receptor and its coactivators, thus leading to escape from hormonal dependence and resistance to antiestrogen therapy are another recent funded domain added to the laboratory.

Our work with HER2-overexpressing tumor cells led us to the observation that the Cdk inhibitor p27 is destabilized by the HER2 kinase, thus leading to dysregulated cell proliferation. Our current work has shown that the serine/threonine kinase Akt can directly phosphorylate p27 in its nuclear localization sequence and induce its retention in the cytoplasm, potentially inhibiting its ability to both block Cdk2 function in the nucleus and to induce growth arrest. Interestingly, however, the complete loss of p27 (in knockout mice) results in a severe alteration in mammary gland morphogenesis, proliferation, and lactation, probably due to impaired cyclin D1/Cdk4 function as a result of complete absence of p27. The impact of p27 gene dosage on oncogene and cyclin D1-induced mammary epithelial transformation is another focus of our work.

In the area of TGFbeta signaling, our working model is that upregulation of TGFb ligands and/or receptors in breast tumor cells provides them with mechanisms that favor their viability by a combination of immunosuppression, induction of angiogenesis and supportive stroma, and drug resistance. Further, autocrine TGFb signaling can be causally associated with the metastatic potential of tumor cells by mediating an epithelial to mesenchymal transition (EMT) and increasing cancer cell motility and survival. We have identified PI3K/Akt and p38MAPK as pathways are required for TGFb-mediated EMT and remain active in identifying other signaling pathways involved in this process. Experimental models and reagents include cells transfected with dominant-negative TGFb receptors, transplantable metastatic breast cancer lines, transgenic mice with temporally-regulated expression of TGFb in the mammary gland, and small molecule inhibitors of the type I TGFb receptor serine-threonine kinase, among others.

Publications:

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