Todd W. Miller, Ph.D.
Assistant Professor of Pharmacology and Toxicology
604 Rubin, HB 7936
One Medical Center Drive
Lebanon, NH 03756
Phone: (603) 653-9284
Research in the Miller Laboratory focuses on the translational application of knowledge of cell signaling pathways to therapeutics for breast cancer. Our work spans the spectrum of basic cancer biology, through translational studies in mouse models and human tissues, and interfaces with clinical trials. We use an array of methods and technologies both in our lab and through interaction with core facilities, including mammalian tissue culture, molecular analyses of gene and protein expression, gene expression microarrays, chromatin immunoprecipitation, next-generation DNA sequencing, bioinformatics, protein microarrays, mass spectrometry, mouse models, and live animal imaging.
One out of every 8 women in the U.S. will develop breast cancer. This year, approximately 200,000 new cases of invasive breast cancer will be diagnosed in the U.S. alone. Of these, ~70% express estrogen receptor alpha (ER) protein. ER is a transcription factor that drives the expression of genes encoding proteins that promote cancer cell growth and survival. While antiestrogen therapies which neutralize ER signaling are effective in many patients, a significant fraction of women exhibit antiestrogen-resistant breast cancer. Understanding mechanisms of antiestrogen resistance and developing novel therapeutic approaches is a major focus of work in our laboratory. One such mechanism of resistance is hyperactivation of the PI3K signaling pathway. PI3K is activated by growth factor receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) at the plasma membrane. PI3K is a central kinase signaling hub that phosphorylates the phospholipid PIP2 to produce PIP3. In turn, PIP3 triggers a signaling cascade that drives cell growth and survival. We showed that inhibition of ER and PI3K signaling synergizes to inhibit growth of ER+ breast cancer cells and induces regression of ER+ breast tumors in mice. Such drug combinations are now being tested in clinical trials.
The second major area of focus in our laboratory is the PTEN/PI3K signaling pathway. Negative regulation of this pathway is conferred by PTEN, which dephosphorylates PIP3. Loss-of-function mutations in PTEN, or loss of PTEN gene expression, results in increased PIP3 levels and pathway activation. PTEN loss is a frequent event in diverse cancer types, and is observed in 25% of breast cancers. While PTEN lipid phosphatase activity is well-studied, PTEN protein phosphatase activity also has tumor suppressive effects which are unresolved. Identifying PTEN protein substrates and the effects of PTEN loss on kinase signaling will reveal novel functions of PTEN, offer candidate phosphoproteins altered by PTEN loss, and unveil new connections between signaling pathways. The RTKs for insulin-like growth factor-1 (IGF-1R) and insulin (InsR) are expressed in the majority of human breast cancers, and early clinical data show promise for IGF-IR/InsR inhibitors as a treatment option. PTEN loss increases IGF-1R/InsR activation. Understanding the effects of PTEN loss on IGF-1R/InsR and PI3K 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-1R/InsR and PI3K pathways which are currently in clinical development.
For a complete listing of publications, visit PubMed.