Research Projects

Transformation of epithelial cells is a multistep process and initiated by driver mutations, however, mutations aren’t just enough, since cells harboring mutations should proliferate to complete the process of tumorigenesis. Adjacent non epithelial cells & or stromal cells play an important role by secreting mitogens that trigger proliferation of mutant cells. We hypothesize that stromal cells in the breast respond to obesity related metabolic disturbances by secreting signaling lipids, which trigger proliferative signaling and activate oncogenic kinase, PAK1, which in turn phosphorylate myriad of substrates including steroidogenic pathway enzyme, Aromatase. Increased aromatase activity in stromal cells leads to increased estrogen production that leads to proliferation of mutant breast epithelial cells leading to tumorigenesis. Estrogen receptor α (ERα) plays a major role in the development of breast tumorigenesis, and its activity is initiated by 17-β estradiol (E2). Obese postmenopausal women exhibit a significant increased risk for developing breast cancer compared with non-obese postmenopausal women. Obesity has been associated with high expression of the enzyme aromatase in the breast adipose tissue, thereby leading to increased local estrogen production, and predisposition to breast hyperplasia and cancer. In breast adipose tissue, aromatase (80–90%) expression is found in adipose stromal cells rather than in mature adipocytes. The key contribution of adipose fibroblasts to a breast tumor is estrogen production via aromatase expression. However, it is widely accepted that signals that arise from the adipose tissue regulate breast tumorigenesis, but a direct mechanistic link about increased estrogen synthesis by aromatase activity and adipocyte function in obese woman remains elusive. Preliminary results from our Mass Spec analysis revealed a signaling kinase - p21-activated kinase 1 (Pak1) - a serine/threonine kinase, is expressed and activated by bioactive lipid molecules in breast adipose tissue, interacts with and phosphorylates aromatase resulting in increased activity and thus, bringing about more estrogen production in the breast. This local increase in estrogen levels is likely to be a triggering event for breast tumor initiation. Therefore, we plan to systematically study the link between increased lipids/adipokines in adipose tissue due to obesity and how it activates Pak1, which in turn modulates aromatase activity and estrogen levels. Our study findings are likely to provide a new regulatory loop in estrogen production in obese individuals and this understanding could be exploited for future therapeutics. Based on the preliminary data and the rationale, our hypothesis is that enhanced aromatase activity and estrogen production in Pak1 activated adipose tissue stromal cells by signaling lipids and adipokines in obese individuals lead to breast tumor initiation.