Transcriptomics,Genomics

Dataset Information

40

Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells


ABSTRACT: Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance Overall design: The transcritomes of naive, Paclitaxel residual and resistant MDA-MB-231 breast cancer cell lines were compared in biological triplicates.

INSTRUMENT(S): [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version]

SUBMITTER: Hauke Busch  

PROVIDER: GSE86839 | GEO | 2017-01-26

SECONDARY ACCESSION(S): PRJNA342666

REPOSITORIES: GEO

altmetric image

Publications

Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

Panayotopoulou Effrosini G EG   Müller Anna-Katharina AK   Börries Melanie M   Busch Hauke H   Hu Guohong G   Lev Sima S  

Oncotarget 20170701 28


Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among the  ...[more]

Similar Datasets

| PRJNA342666 | ENA
2013-04-03 | E-GEOD-36938 | ArrayExpress
2011-07-01 | GSE25613 | GEO
2011-07-01 | E-GEOD-25613 | ArrayExpress
2013-01-15 | E-GEOD-43502 | ArrayExpress
2008-05-01 | GSE10841 | GEO
2008-06-19 | E-GEOD-10841 | ArrayExpress
2015-12-10 | E-GEOD-54772 | ArrayExpress
2012-03-01 | E-GEOD-33827 | ArrayExpress
2011-07-18 | E-GEOD-12791 | ArrayExpress