Revealing the Potential for mSWI/SNF as Biomarkers in Breast Cancers
Abstract
Decades of research have advanced our understanding of breast cancer and improved treatment options, but we are still far from living in a world where every breast cancer is curable. Cancers present genomic alterations that, ultimately, transform the cell and lead to the disease. Therefore, understanding the consequences of such alterations is of great help in the fight against cancer. Epigenetic factors present high genomic alterations in all types of cancers. These factors have roles in the cell nucleus, where our DNA is stored. Among them, the SWI/SNF complexes are altered in 40% of breast cancers. While recent studies start to shed light on the therapeutic potential behind these complexes’ functions in cancers, their normal and cancer-associated mechanisms are still not well understood. Advancing this scientific knowledge will help save lives and advance toward a world without breast cancers. We uncovered that cancer cell lines harboring genomic alterations in SWI/SNF are more sensitive to specific drugs when compared to other cancer cell lines. All these drugs, directly or not, target protein synthesis. Protein synthesis takes place in the cell cytoplasm. This cellular mechanism allows rapid adaptation to various stimuli and is highly altered in cancers. For example, cancer cells adapt to the need of sustained proliferation by increasing global protein synthesis and/or synthetizing specific proteins essential to the development of the disease and to combat therapy. Furthermore, protein synthesis is key to a cell’s response to stress. Within the tumor microenvironment, cancer cells are exposed to various stresses, such as a lack of oxygen and nutrients. These stresses, and, consequently, cancer cell’s responses to these stresses, were shown to drive the disease by leading to tumorigenesis, metastasis, and resistance to therapy. How could SWI/SNF complexes, epigenetic factors with known roles in the cell nucleus, be linked to protein synthesis that takes place in the cell cytoplasm? Our preliminary data demonstrate that these complexes are also in the cell cytoplasm and have roles in protein synthesis. While the current literature focuses on these complexes’ roles in the nucleus, we pioneer the study of their roles in the cytoplasm. We propose that SWI/SNF complexes have direct breast cancer-relevant roles in protein synthesis within the cytoplasm, that differ from their established roles in the nucleus, thus revealing new biomarkers for therapies impacting protein synthesis and greatly expanding the frontier of personalized therapy. This proposal addresses two Fiscal Year 2022 Breast Cancer Research Program overarching challenges, Identify what drives breast cancer growth; determine how to stop it and Identify why some breast cancers become metastatic, by focusing on two questions: What are the consequences of SWI/SNF’s breast cancer alteration on protein synthesis under breast cancer-relevant stresses? Could these roles lead to the establishment of SWI/SNF as biomarkers in specific subtypes of breast cancers or during disease progression such as metastasis? Under the first aim, we will modify normal breast epithelial cells to mimic the two main SWI/SNF alterations we observed in 95% of our breast tumor samples to characterize the consequences of these alterations on protein synthesis under lack of oxygen or nutrients. Under the second aim, we will examine 500 tumors from 200 breast cancer patients to determine the correlation between protein synthesis, stresses, and expression and localization (nucleus or cytoplasm) of SWI/SNF. Our preliminary data highlights the fact that SWI/SNF are altered in all breast cancer subtypes, including triple-negative, and across all disease stages (primary tumor, local recurrence, metastasis). Therefore, our proposal has great potential to impact many breast cancer patients. Therapies targeting protein synthesis are already used in the clinic and could gain more
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310129
Entities
People
- Gregory R Bean
Organizations
- Stanford University
- United States Army