The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers

Todd W. Miller, Ph.D.

Research Associate Professor of Cancer Biology
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
771 Preston Research Building
Nashville, TN 37232-0146
615-936-1925

Profile

RESEARCH SPECIALTY Endocrine resistance, estrogen receptor signaling, and RTK/PI3K/PTEN signaling in breast cancer RESEARCH DESCRIPTION Our work focuses on three major themes in breast cancer: 1) mechanisms of resistance to endocrine therapies, 2) modulation of kinase signaling by the tumor suppressor phosphatase PTEN, and 3) the role of growth factor receptor tyrosine kinase signaling in 1 and 2.
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RESEARCH SPECIALTY

Endocrine resistance, estrogen receptor signaling, and RTK/PI3K/PTEN signaling in breast cancer

RESEARCH DESCRIPTION

Our work focuses on three major themes in breast cancer: 1) mechanisms of resistance to endocrine therapies, 2) modulation of kinase signaling by the tumor suppressor phosphatase PTEN, and 3) the role of growth factor receptor tyrosine kinase signaling in 1 and 2. Our goals are to discover novel drug targets for the treatment of patients with endocrine-resistant disease, and to further our understanding of the roles of estrogen receptor ¿ and RTK/PI3K/PTEN signaling in breast cancer.

Two-thirds of breast cancers express estrogen receptor ¿ (ER) and/or progesterone receptor (PR), which typically indicates that breast cancer cells depend upon estrogens for growth. Preferred therapies for such patients target ER signaling, either by antagonizing ligand binding to ER (tamoxifen), downregulating ER (fulvestrant), or blocking estrogen biosynthesis (aromatase inhibitors, AIs). Although endocrine therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit de novo or acquired resistance, and disease eventually recurs in a significant fraction of treated patients. These metastatic recurrences are uniformly incurable. Mechanisms of escape from endocrine therapy are unknown for the vast majority of patients with ER/PR+ disease. We have demonstrated that loss of the PTEN tumor suppressor gene, a common mutation in cancer which activates the PI3K signaling pathway, confers resistance to antiestrogenic therapies. We have also investigated mechanisms of acquired resistance to aromatase inhibitor therapy. We found that the PI3K pathway was upregulated upon adaption of ER+ breast cancer cells to estrogen-depleted conditions, and cells showed sensitivity to PI3K inhibitors. We also identified the insulin-like growth factor-I receptor (IGF-IR)/insulin receptor (IR), ER, and CDK4 pathways as critical for estrogen-independent breast cancer cell growth. Therefore, cotargeting the IGF-IR/IR, PI3K, ER, and CDK4 pathways may benefit patients with cancer that is resistant to endocrine therapy.

Deficiency in the expression or function of the phosphatase PTEN is one of the most frequently occurring aberrations in cancer. While the primary tumor suppressive function of PTEN is thought to be as a lipid phosphatase which antagonizes PI3K signaling, PTEN also acts as a protein phosphatase. However, the putative tumor suppressor function of PTEN protein phosphatase activity is unclear. Global profiling of PTEN protein substrates and the effects of PTEN loss on kinase signaling will identify novel functions of PTEN, offer
candidate phosphoproteins altered by PTEN loss, and reveal new connections between signaling pathways. We found that PTEN loss increases the activation of IGF-IR/IR. IGF-IR is expressed in the majority of human breast cancers, and early clinical data show promise for IGF-IR/IR inhibitors as a treatment option. Identification of the effects of PTEN loss on IGF-IR/IR signaling and sensitivity to therapeutics will reveal novel roles of PTEN, and whether PTEN status is a biomarker of response to therapy. In turn, these collective findings will allow the optimization of therapies targeting the IGF-IR/IR and PI3K pathways which are currently in clinical development.

 

Education

University of Connecticut, B.S.

University at Albany, Ph.D.


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