Dataset Information

Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors

ABSTRACT: Metaplastic breast carcinoma (MBC) is the most aggressive form of triple-negative cancer (TNBC), defined by the presence of “metaplastic” components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantified 5,798 proteins in MBC, TNBC, and normal breast from 27 patients. MBC showed increased epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways compared to TNBC. MBC subtypes exhibited distinct upregulated profiles; translation and ribosomal events in spindle, inflammation and apical junctions in squamous, and extracellular matrix in sarcomatoid. Comparison of the proteomes of spindle MBC with MMTV-cre;Ccn6fl/fl spindle MBC tumors revealed a shared spindle-specific signature of 17 upregulated proteins involved in translation (e.g. RPL4,6,18, P3H1, PYCR1) and 19 downregulated proteins with roles in cell metabolism (e.g. ADH1B, ADH1C, LIPE, SOD1, FABP4). These data identify subtype specific MBC protein profiles providing biomarkers and therapeutic targets.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Mammary Gland

DISEASE(S): Breast Cancer

SUBMITTER: Sabra Djomehri

LAB HEAD: Celina G. Kleer

PROVIDER: PXD014414 | Pride | 2020-04-22

REPOSITORIES: Pride

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Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors.

Djomehri Sabra I SI Gonzalez Maria E ME da Veiga Leprevost Felipe F Tekula Shilpa R SR Chang Hui-Yin HY White Marissa J MJ Cimino-Mathews Ashley A Burman Boris B Basrur Venkatesha V Argani Pedram P Nesvizhskii Alexey I AI Kleer Celina G CG

Nature communications 20200407 1

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific in ...[more]

PMID: 32265444

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Project description:Purpose:Triple negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis with limited therapeutic options. TNBC frequently harbors BRCA mutations translating to platinum sensitivity; platinum response may be augmented by additional suppression of DNA repair mechanisms through poly(ADP-ribose)polymerase (PARP) inhibition. We evaluated brain penetrance and efficacy of Carboplatin +/- the PARP inhibitor ABT888, and investigated gene expression changes in murine intracranial (IC) TNBC models stratified by BRCA and molecular subtype status. Experimental design:Athymic mice were inoculated intra-cerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low), or BRCA-wild-type: MDA-MB-468 (basal), MDA-MB-231BR (claudin-low) TNBC cells and treated with PBS control (IP, weekly), Carboplatin (50mg/kg/week, IP), ABT888 (25mg/kg/day, OG), or their combination. DNA-damage (?-H2AX) and apoptosis (cleaved-Caspase-3(cC3)) were assessed via IHC of IC tumors. Gene expression of BRCA-mutant IC tumors was measured. Results: Carboplatin+/-ABT888 significantly improved survival in BRCA-mutant IC models compared to control, but did not improve survival in BRCA-wild-type IC models. Carboplatin+ABT888 revealed a modest survival advantage versus Carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436 but not in the SUM149 model. BRCA-mutant SUM149 expression of ?-H2AX and cC3 proteins was elevated in all treatment groups compared to Control, while BRCA-wild-type MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene expression changes in BRCA-mutant models.Conclusions: Carboplatin+/-ABT888 improves survival in BRCA-mutant IC TNBC models with corresponding DNA damage and gene expression changes. Combination therapy represents a promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. reference x sample

Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.

Dataset Information

Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors

Publications

Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors.

Similar Datasets

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