Although cancer is a leading cause of mortality for women in the U.S., the initiating triggers are mainly unknown, thus some women's cancers remain idiopathic and the origins continue to evade understanding. Susceptibility to oncogenesis may be caused by deregulation of non-coding RNAs, since these small molecules have large regulatory roles in the cell. A major goal of this research proposal is to generate non-coding RNA biomarkers to assist in the early detection and prevention of cancer through the indication of a predisposition to malignancy. To achieve this goal, we propose a hypothesis whereby alterations of microRNAs (miRNAs) are implicated in driving the development of obesity-related women's cancers, such as breast and ovary. Another major goal of this research proposal is to define the molecular mechanism involved. Using a mouse model of late-onset obesity that is unrelated to diet and results in subsequent spontaneous cancer development, we plan to test our central hypothesis: autotaxin-induced enhancement of oncogenic growth factor signaling mediated by lysophosphatidic acid (LPA) occurs in adipocytes and pre-malignant cells and is causal for carcinogenesis. Further, a stepwise mechanism results in an alteration of autotaxin and LPA receptor expression and function in adipocytes, which affects growth factor signaling to the surrounding cells and yields a measurable alteration of specific regulatory miRNAs secreted. We predict this phenomenon can be quantified in plasma since miRNAs are stably secreted into extracellular exosomes, microsomes or bound to Argonaut proteins. We have previously shown miR- 30c-2-3p participates in a regulatory feedback loop to inhibit oncogenic transcripts that are initiated by LPA-mediated receptor activation. Moreover, miR-30c-2-3p expression and function is abnormal in many ovarian cancer cells. We predict miR-30c-2-3p (and the miR-30 family members) will be measurably altered in our obese mouse model, which is the goal of our first specific aim.
Our second aim seeks to define the stepwise molecular mechanism and understand the molecular relationship between adipocytes and cancer cells, whereby miR-30c-2-3p regulates cancer cell proliferation. In our third specific aim, we seek to quantify specific miRNAs in an otherwise healthy human population in order to determine whether they are altered as a consequence of body mass index and could provide a measurable biomarker for susceptibility. These studies could define an identifiable pre- condition by measuring modulations in non-coding RNA prior to the onset of women's cancer. Characterization of the molecular mechanism and stepwise pathway leading to tumorigenesis should improve our understanding of how diet-unrelated, late-onset obesity drives cancer development and uncover novel opportunities for therapeutic modulation.
This project is relevant to public health because it investigates microRNAs that are likely involved in cancer predisposition induced by enhanced autotaxin (ATX) and lysophosphatidic acid (LPA) signaling that manifests in late-onset obesity among women. The project will determine whether measuring microRNAs in a specimen indicates this condition. It also defines the ATX/LPA/miR30c-2-3p signaling pathway in regulating cancer cell growth and obesity.
