Note that the citation numbers refer to the papers listed on the "Publications" page.
Overview – We study the Epidermal Growth Factor (EGF) family of peptide hormones and their receptors, the ErbB receptor tyrosine kinases. This network regulates the proliferation and differentiation of epithelial cells and deregulated signaling by this network contributes to human tumorigenesis and increased tumor cell invasiveness, metastatic potential, and chemoresistance. Consequently, we seek to understand the mechanism by which this network regulates cell function, with the ultimate goal being the development of novel cancer treatments.
Mechanisms of ERBB4 signaling – We have demonstrated that ERBB4 homodimers function as tumor suppressor proteins, whereas ERBB4-EGFR and ERBB4-ERBB2 heterodimers function as oncogenes. We are focused on deciphering the mechanisms by which ERBB4 can be coupled to these divergent responses [19, 25, 26, 41, 44, 50, 56]. We are also pursuing the discovery and development of novel ERBB4 agonists and antagonists that can be used to pharmacologically probe ERBB4 function in human malignancies and hold potential for the treatment of ErbB4-dependent tumors [30, 36, 42, 46, 55].
EGF family hormones – We are characterizing the biological activities of EGF family hormones and we are identifying factors that regulate the affinity, potency, and efficacy (intrinsic activity) of these peptide growth factors [20, 23, 24, 29, 30, 32, 34, 36, 40, 42, 45, 46, 51].
ERBB4 in human tumors – We have written a comprehensive review of the roles that ERBB4 plays in human tumors . That review has identified several projects underway in our laboratory. Metastatic melanomas that possess wild type (WT) BRAF alleles are particularly deadly, as they do not respond to BRAF inhibitors, MEK inhibitors, or other targeted chemotherapeutics. Our preliminary data indicate that ERBB4 heterodimers function as oncogenes in human melanoma cell lines that possess BRAF WT alleles. We are developing in silico methods to assess whether ERBB4 mutations found in BRAF WT melanoma samples function are likely to function as melanoma drivers. We are utilizing in vitro and in vivo model systems to define the roles of ERBB4 overexpression, ERBB4 heterodimerization partners, ERBB4 ligands, and ERBB4 mutations in BRAF WT human melanoma. Similar but less advanced efforts are underway to determine the role of ERBB4 signaling in human childhood brain tumors and triple negative cancers.