This R21 project aims to identify and characterize novel targets and biomarkers involved in a previously unrecognized cellular mechanism promoting the rapid decay of oncogenic transcripts. While all proteins in a cell are produced from their respective transcripts (mRNAs), those encoding cancer promoting proteins typically carry unique distinguishing features in their 3'untranslated regions. These distinguishing features of oncogenic mRNAs allow for their stability and overexpression (e.g. during cancer development), or for their decay and destruction (e.g. during normal tissue maturation). Our preliminary research has shown that destruction of the cancer promoting mRNA occurs while it is polyribosome associated and where proteins are subject to post-translational modifications like acetylation. Importantly, compartmentalization of this mRNA destruction machinery to the polyribosome facilitates a search for protein isoforms that regulate this switch, revealing novel cancer therapeutic targets. It is known that epigenetic therapy such as histone deacetylase inhibition rapidly induces accelerated decay of ERBB2 and other oncogenic transcripts, putatively via induction of polysome protein post-translational modifications. The first project aim is to isolate and identify by mass spectrometry (MS) polyribosome protein isoforms from breast cancer cells that have their oncogene transcript destruction switch activated by histone deacetylase inhibition. The second project aim is to validate candidate polyribosome protein targets that are demonstrated to be essential in regulating cancer growth as well as the oncogene transcript destruction mechanism, using the technique of RNA interference (RNAi). This project will generate a list of fully characterized, validated, and prioritized polyribosome protein targets and biomarkers known to regulate cancer growth and oncogene transcript stability. This list will contain the most promising polyribosome isoforms for prediction and targeting of an entirely new class of cancer therapeutics that selectively turn off cancer-promoting proteins by inducing their transcript decay.
A priority issue for cancer research is the need for more innovative cancer treatment strategies and their companion predictive biomarkers. The hypothesis underlying this proposal is that an entirely new cancer treatment strategy can be developed based on targeting key components in a previously unrecognized cellular mechanism within polyribosomes that regulates a switch determining either oncogene transcript stability or its destruction. Using a sensitive and recently developed polysome profiling and mass spectrometry-based approach, we will discover and confirm the role of novel polysome protein isoforms that regulate this switch. The discovery and validation of these novel therapeutic targets and predictive biomarkers will drive the development of an innovative class of cancer therapeutics capable of selectively turning off cancer-promoting proteins by accelerating their transcript decay.
|Troester, Melissa A; Hoadley, Katherine A; D'Arcy, Monica et al. (2016) DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from The Cancer Genome Atlas. NPJ Breast Cancer 2:16007|
|Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V et al. (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17:1049-61|
|Hoadley, Katherine A; Yau, Christina; Wolf, Denise M et al. (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:929-944|
|Goncalves, Renata L S; Rothschild, Daniel E; Quinlan, Casey L et al. (2014) Sources of superoxide/H2O2 during mitochondrial proline oxidation. Redox Biol 2:901-9|
|Zawadzka, Anna M; Schilling, Birgit; Cusack, Michael P et al. (2014) Phosphoprotein secretome of tumor cells as a source of candidates for breast cancer biomarkers in plasma. Mol Cell Proteomics 13:1034-49|
|Wilson-Edell, Kathleen A; Yevtushenko, Mariya A; Rothschild, Daniel E et al. (2014) mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms. Breast Cancer Res Treat 144:287-298|
|Lal, Aseem; Chan, Loretta; Devries, Sandy et al. (2013) FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast. Breast Cancer Res Treat 139:381-90|
|Sadanandam, Anguraj; Lal, Aseem; Benz, Stephen C et al. (2012) Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells? Breast Cancer Res Treat 136:693-703|