Research Interests

Embryonic Patterning Pathways in Mammary Development
and Breast Cancer

Mammary glands form in the embryo but also undergo extensive postnatal ductal development during puberty.  Each pregnancy induces further cyclical rounds of proliferation and differentiation in preparation for lactation followed by apoptosis, and extensive remodeling after weaning. Mammary development is regulated temporarily by hormones but spatially by hormonally-induced localized paracrine factors. We study the roles of Wnt/b-catenin and Hedgehog/Gli pathways in this process.

b-catenin is a multifunctional protein involved in cadherin-mediated cell adhesion at the plasma membrane and transcriptional regulation in the nucleus. Cadherin-catenin complexes are essential for maintaining epithelial integrity in the developing mammary gland. Their loss or transient downregulation occurs frequently in human breast cancer and facilitates invasion and metastasis. Numerous signaling pathways regulate the stability of cytosolic b-catenin, the best understood being the canonical Wnt pathway. Wnts signal by stabilizing cytosolic b-catenin and promoting its nuclear entry and transcriptional function. Wnt/b-catenin signaling regulates normal mammary stem cell dynamics and is thus essential for many different stages of embryonic and postnatal mammary development. Our work has shown that deregulated b-catenin signaling leads to mammary stem and progenitor cell accumulation, precocious development and breast cancer in mice. Recent studies suggest that a similar link exists between reactivation of developmental pathways and human breast cancer. Elevated b-catenin signaling is particularly prevalent in metaplastic and basal subtypes of breast cancer, which have the worst prognosis and patient outcome. Deregulated b-catenin signaling can occur by other signaling routes, and importantly many of these pathways are aberrant in breast cancer and when disturbed also cause mammary developmental abnormalities.

In addition we study the role of the Hedgehog/Gli pathway in the mammary gland and our work has shown that repression of Hedgehog signaling is critical for normal embryonic mammary development.  Misactivation of this pathway in the embryo leads to loss of mammary buds.  Currently we are studying the effects of derepressing this pathway during adult mammary development and our studies have shown that this event is critical for Wnt tumor induction