Pamela Cowin

Links Between Mammary Development and Breast Cancer

Our objective is to understand the biological links between mammary development and breast cancer.  We seek to illuminate the mammary lineage and identify markers of potential translational utility in tracking and eradicating breast cancers.

Mammary glands, like teeth, hair and sweat glands, emerge in the embryo as appendages of the ectoderm.  By birth they constitute a small branched tree that is extended during puberty to form the permanent gland. Extensive branching and clusters of alveoli form occurs with each pregnancy in preparation for lactation.  These temporary structures are removed after weaning through a process of involution and must be regenerated with every pregnancy. Each of these developmental stages is associated with heightened risk for breast cancer. This increased risk relates first, to the repeated cycles of stem and progenitor amplification that render the cells susceptible to replicative error, and second, to incomplete removal of such transformed cells during involution.

Mammary development is regulated temporally by hormones but spatially by local paracrine factors such as Wnts and TGF-beta.  We have studied the roles of Wnt/beta-catenin and Hedgehog/Gli pathways in these processes and linked their action to stem and progenitor cell amplification and lineage commitment/skewing in the normal and pathological situations respectively.

In recent years we have pioneered two research areas that combine our expertise in basic cell adhesion mechanisms with mammary biology.  In one, we investigate the role of Latent TGF-beta Binding Protein (LTBP1) in mammary development and its contribution to breast cancer metastasis. In the second, we explore the role of a novel adhesion-GPCR in mammary development and breast cancer.  We have developed unique genetically modified mouse models that allow us to track cells that express this GPCR expression, trace their lineage, kill them and examine the consequences for the mammary lineage and development and will determine their requirement for tumor susceptibility and progression.