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Paclitaxel resistance in triple negative breast cancer involves novel functional genomic aberrations in the ABCB1 gene.

ABSTRACT: Five Triple Negative Breast Cancer cell lines were exposed to increasing concentration of Paclitaxel untill they acquired resistance. In order to identify changes in gene expression associated with resistance to PTX, we performed gene expression profiling on parental and resistant cell lines. Of ~22000 genes surveyed by microarray analysis, 5.0%, 3.7%, 9.0%, 7.3%, and 5.4% of the genes showed changes in expression of 2-fold or greater (p value < 0.05) in BT20, SUM149, MDA-MB-231, MDA-MB-436 and MDA-MB-468 cell lines, respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90564 | GEO | 2017/02/28

SECONDARY ACCESSION(S): PRJNA355042

REPOSITORIES: GEO

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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:Cultured cancer cells exhibit substantial phenotypic heterogeneity when measured in a variety of ways such as sensitivity to drugs or the capacity to grow under various conditions. Among these, the ability to exhibit anchorage-independent cell growth (colony forming capacity in semisolid media), has been considered to be fundamental in cancer biology, because it has been connected with tumor cell aggressiveness in vivo such as tumorigenic and metastatic potentials, and also utilized as a marker for in vitro transformation. Although multiple genetic factors for anchorage-independence have been identified, the molecular basis for this capacity is still largely unknown. To investigate the molecular mechanisms underlying anchorage independent cell growth, we have used genome-wide DNA microarray studies to develop an expression signature associated with this phenotype. Using this signature, we identify a program of activated mitochondrial biogenesis associated with the phenotype of anchorage-independent growth and importantly, we demonstrate that this phenotype predicts potential for metastasis in primary breast and lung tumors. Keywords: Breast cancer cell lines with various colony-forming ability To develop an expression signature reflecting the capacity for anchorage-independent cell growth, we first carried out colony formation assays with 19 breast cancer cell lines in suspension culture dish with methyl-cellulose containing media. Starting with 20,000 plated cells, five cell lines (MDA-MB-361, HCC38, ZR75, Hs578T and BT483) gave rise to less than 20 colonies, while 8 cell lines (MCF7, MDA-MB-231, BT20, SKBR3, MDA-MB-435s, T47D and BT474) showed formation of more than 500 colonies. The rest of the cell lines showed an intermediate phenotype in colony forming ability (20-200 colonies; HCC1143, HCC1806, HCC1428, MDA-MB-453, CAMA1, BT549 and MDA-MB-157). Among 19 cell lines, 11 cell lines have duplicates of expression data in a different batch. We removed the batch effect of this Affymetrix expression data using ComBat according to the instruction of http://statistics.byu.edu/johnson/ComBat/Abstract.html. Therefore, this dataset is a combined and standardized data that are originally RMA formatted.

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Paclitaxel resistance in triple negative breast cancer involves novel functional genomic aberrations in the ABCB1 gene.

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