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Pamela CowinProfessor, Department of Cell Biology
Professor, Ronald O. Perelman Department of Dermatology
550 First Avenue
New York, NY 10016
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/beta-catenin and Hedgehog/Gli pathways in this process.
Beta-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 beta-catenin, the best understood being the canonical Wnt pathway. Wnts signal by stabilizing cytosolic beta-catenin and promoting its nuclear entry and transcriptional function. Wnt/beta-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 I?-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 beta-catenin signaling is particularly prevalent in metaplastic and basal subtypes of breast cancer, which have the worst prognosis and patient outcome. Deregulated beta-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.
Research Keywordscell adhesion and Wnt signaling, developmental genetics, genome integrity, stem cell biology
Highlighting Kathleen Green and Mario Delmar, Guest Editors of Special Issue (part 2): Junctional Targets of Skin and Heart Disease
Cowin, Pamela. Highlighting Kathleen Green and Mario Delmar, Guest Editors of Special Issue (part 2): Junctional Targets of Skin and Heart Disease. Cell communication & adhesion. 2014 Jun;21(3):101-102 (1013482)
Bringing law and order to the cytoskeleton and cell junctions: An interview with Werner Franke
Cowin, Pamela. Bringing law and order to the cytoskeleton and cell junctions: An interview with Werner Franke. Cell communication & adhesion. 2014 Jun;21(3):103-107 (1013492)
Highlights from special issue: junctional targets of skin and heart diseases
Delmar, Mario; Green, Kathleen; Cowin, Pamela. Highlights from special issue: junctional targets of skin and heart diseases. Cell communication & adhesion. 2014 Feb;21(1):1-1 (833232)
Adhesion g-protein-coupled receptors: elusive hybrids come of age
Simundza, Julia; Cowin, Pamela. Adhesion g-protein-coupled receptors: elusive hybrids come of age. Cell communication & adhesion. 2013 Dec;20(6):213-226 (681042)
Highlighting Young Investigators: Guest Editor Ramanuj DasGupta Ram DasGupta: Pushing the boundaries of beta-catenin signaling and drug development
Cowin, Pamela. Highlighting Young Investigators: Guest Editor Ramanuj DasGupta Ram DasGupta: Pushing the boundaries of beta-catenin signaling and drug development. Cell communication & adhesion. 2013 Dec;20(6):151-153 (681052)