Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.
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ABSTRACT:
SUBMITTER: Krug K
PROVIDER: S-EPMC8077737 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Karsten Krug, Eric J. Jaehnig, Shankha Satpathy, Lili Blumenberg, Alla Karpova, Meenakshi Anurag et al., (2020) <a href="https://www.cell.com/cell/fulltext/S0092-8674(20)31400-8" target="_blank">Cell, 183, 1436-1456</a><br>DOI: https://doi.org/10.1016/j.cell.2020.10.036<br><br><p>The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Herein this "proteogenomic" approach was applied to 122 treatment-naive primary breast cancers purposely accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy and allowed more accurate assessment of Rb status for the prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomic profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for the clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.</p><p><em>Genomic Data</em> for Breast Cancer tumors is available from the NCI Genomic Data Commons (GDC), <a href="https://portal.gdc.cancer.gov/projects/CPTAC-2" target="_blank">here</a><br><em>Gene Expression data</em> in GCT file format is available under the metadata section below<br><em>Proteomic Data Analysis</em> for Breast Cancer tumors (PSMs and Summary Reports) is available from the CPTAC Common Data Analysis Pipeline (Study S039 Early Data Release), <a href="/study-summary/S039" target="_blank">here</a>
<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/study-summary/S060">https://cptac-data-portal.georgetown.edu/study-summary/S060</a> on 06/05/21</li></ul>
2021-06-05 | MSV000087576 | MassIVE
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Project description:Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus. Although still considered incurable by currently available treatment modalities, many patients with MBC nowadays enjoy several years of good quality life coupled with decent tumor control. The diversity of therapies and unusual pattern of side effects can be quite perplexing to the treating physician. The sequence of variable agents and management of side effects, in addition to the timing of initiation of cytotoxic chemotherapy, is among the challenges faced by oncologists. In this review, we shed a spotlight on mechanisms of resistance to ET, and provide a review of landmark studies that have recently reshaped the landscape of treatment options for patients with metastatic HR-positive, HER2-negative MBC. A suggested treatment strategy for newly diagnosed patients is also discussed herein.
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