Coordinated Regulation of Breast Cancer Cell Growth and Metabolism through Inhibition of Nonproteolytic K63 Ubiquitination
Abstract
Overarching Challenge: This project will address the overarching challenge of "what drives breast cancer growth; determine how to stop it" by identifying and characterizing a novel tumor suppressor. Rationale and Objective: Molecular profiling of large tumor sets has led to the identification of G-Protein Suppressor 2 (GPS2) as a significantly mutated gene in breast cancer, medulloblastomas, and leukemias. In normal cells, GPS2 plays an important role in the regulation of inflammation and lipid metabolism. In cancer cells, it is proposed to act as a putative tumor suppressor. However, its functions in preventing cancer development and/or progression are unknown. The main goal of this proposal is to dissect the role of GPS2 as a tumor suppressor factor in breast cancer. Our working hypothesis is that GPS2 plays a critical and unexpected role in the coordinated regulation of multiple pathways that control cell growth, survival, and metabolism. Aberrant regulation of these pathways, upon GPS2 loss, promotes the synergistic activation of cellular and metabolic adaptations that sustain tumor growth, development, and resistance to hormonal therapies. What types of patients will it help and how: Characterization of previously unappreciated oncogenes and tumor suppressor is a critical area of cancer research, which has the potential of benefitting all kind of patients by providing new therapeutic windows of opportunity. In this regard, there is extra value in studying GPS2, as we hypothesize that GPS2-mediated inhibition of Ubc13 activity could be a key regulatory strategy at the intersection of multiple pathways controlling cell growth and metabolism. Thus, the successful completion of the proposed studies has the potential of highlighting a previously unexplored, and potentially targetable, node of regulation. In addition, the proposed studies could identify GPS2 (and/or other proteins in its regulatory network) as a useful biomarker to predict patients response to endocrine and combination treatments. Most early-stages breast cancers are estrogen receptor (ER)-positive and can be effectively treated with adjuvant hormonal therapies relying on either blocking the endogenous estrogen production or inhibiting estrogen s actions. However, this approach is limited in patients with pre-existing or acquired resistance to endocrine treatments. Treatments with drugs targeting other growth-promoting pathways are currently under investigation, alone or in combination with anti-estrogenic compounds, as a way to overcome endocrine resistance. However, there is a need for predictive biomarkers of treatment outcome. In this context, the patients that are more likely to benefit directly from these studies are those with deletions/mutations or misregulation of GPS2 activity. Likely impact in ending breast cancer and projected time to achieve patient-related outcomes: The Breast Cancer Research Program s vision of ending breast cancer is one that can be achieved only through the combined success of many innovative approaches. I anticipate the results obtained under this award to critically contribute towards this endpoint goal. This 3-year project will first validate the proposed tumor suppressor role for GPS2 in vitro and in vivo in mouse models, and second fully characterize the molecular basis of its tumor suppressing actions. The next steps would involve investigating GPS2 expression and activation in human samples, confirm its usefulness as a biomarker, and use the information gained from the studies conducted under this award to design new therapeutic approaches that modulate GPS2 function directly or through the actions of enzymes that control its subcellular localization.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710048
Entities
People
- Valentina Perissi
Organizations
- Boston University Medical Campus
- United States Army