Potential treatment targets in the whole-tissue proteome of triple negative breast cancer
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Breast Cancer Cell
DISEASE(S): Breast Cancer
SUBMITTER: 
Daniel Bucio Noble
LAB HEAD: Prof. Roger Reddel
PROVIDER: PXD048791 | Pride | 2026-06-01
REPOSITORIES: Pride
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Project description:Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, we used gene expression profiling and immunohistochemistry to eluicidate potential differences between TNBC tumors of EA and AA patients on a molecular level. WG-DASL experiment of 90 FFPE samples of ER, PR and HER2 (triple) negative breast cancer samples diagnosed between 1987 and 2007. Invasive disease was identified on H&E sections by the study pathologist and one to three 1.5 mm cores were punched from the top down in the designated tumor areas of each FFPE block. The cores were deparaffinized with xylene at 50°C for 3 minutes. RNA was extracted using the RecoverAll Total Nucleic Acid Isolation kit (Applied Biosystems) following the manufacturer's protocol. The isolated RNA was hybridized to Whole-Genome DASL (HumanRef8 V 3.0, Illumina) at the Yale Center for Genome Analysis. 90 primary tumor RNA samples from 90 patients were adequate for analysis and passed Quality control.
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Project description:<p>Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies, including triple-negative breast cancer (TNBC). Here, we investigate the essential metabolic adaptations that support mitochondrial quality control in cancer cells with the aim to uncover therapeutically actionable metabolic vulnerabilities. Using TNBC as a model system and an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, together with functional experimental analyses, we detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of this sphingolipid pathway in cancer cells via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human cell-line derived xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.</p>
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