Although each cell of a multicellular organism shares the same genetic information with every other cell, emergence of new information is essential for successful organ development and their maintenance throughout the life span of an organism. We will combine hypothesis and discovery driven approaches to decipher the critical genetic and epigenetic events that coordinate the development and maintenance of organs, and how these processes are deregulated in human diseases.
Mechanisms of Mammary Gland Development & Breast Cancer
Mechanisms that govern the maintenance of architecture and differentiated state of organs are deregulated in cancer. Mammary glands are one of the few organs that can undergo repeated cycles of remodeling and morphologic alterations. In each cycle there are ample opportunities for the complex remodeling mechanisms of the mammary gland to go wrong and cause breast cancer, the second leading cause of cancer-related mortalities in women. As the initial onset and progression of breast cancer are poorly understood, my laboratory’s long-term goal is to elucidate genetic and epigenetic mechanisms that modulate the plasticity of mammary gland architecture and functions. This may lead to better preventive and therapeutic strategies, a critical aspect to furthering the current success in breast cancer management.
In breast cancer the basic unit of mammary gland architecture, the acinus, becomes malignant and loses its structural integrity. Using organotypic assays (3D culture), we have discovered that G1P3, one of the first identified interferon (IFN) stimulated genes (ISGs) perturbs the architecture of normal acini by inhibiting the apoptosis of acinar luminal cells to cause hyperplasia. In breast cells in additions to IFNs, the expression of G1P3 was also induced by estrogen. In agreement with these results G1P3 was overexpressed in early and advanced stages of breast cancers. More importantly, elevated expression of G1P3 significantly associated with poor outcomes in ER+ breast cancer, which highlights the clinical relevance of G1P3. Thus, we have uncovered a new arm of signaling used by immuno-endocrine pathways to disrupt cell and tissue architecture, which challenges the dogma of IFNs as the tumor suppressors of the innate-immune network. This sparked a desire to understand the functions of G1P3 and other interferon stimulated genes in modulating the relationship between tissue architecture and cellular functions in normal and diseased conditions. Our current efforts are focused on: 1) How does G1P3 modulate epithelial cell polarity and tissue organization? 2) Role of G1P3 in breast cancer development and progression, and 3) Role of G1P3 in modulating survival functions in immuno-endocrine signaling pathways.