Grant: Operating Grant

Breast cancer is a leading cancer in women; it is estimated that over 23,000 Canadian women will be diagnosed, and over 5,000 will die from it this year. Breast cancer is characterized by both over-growth and loss of tissue organization. In normal mammary glands, cells that form ducts have a characteristic top-bottom organization, which is essential for normal function and is disrupted in cancers. The mammary gland is an exceptional model to understand how cells maintain normal organization during development, in which cells grow and invade the surrounding tissue in a controlled manner to generate the mammary gland. We think similar mechanisms underlay cancer growth and the invasion of tumor cells into surrounding tissue, but that these cells have lost critical regulatory systems. The primary objective of my research program is to understand the mechanisms by which normal mammary glands develop, and how these same systems may be hijacked for cancer progression. In the current proposal, we are investigating an enzyme called atypical protein kinase C (aPKC), which is a crucial organizer of cell organization. The expression of this protein is disrupted in breast cancer, and we previously demonstrated that is essential for normal mammary development. We will examine the mechanism by which aPKC regulates normal invasion and branching of ducts during development by manipulating the expression of aPKC in mice, using techniques we previously established involving stem cell transplants and mammary regeneration. We will examine effects on cell movements and stem cell renewal, and characterized important substrates for the aPKC enzyme. We will also examine a role for aPKC in breast cancer progression by altering its expression in established mouse model of human HER2/ErbB2+ breast cancer to determine whether it affects tumor growth and metastasis.