Unknown,Transcriptomics,Genomics,Proteomics

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Differential expression of genes involved in the transtion to Doxorubicin drug resistance in MCF7 breast cancer cells

ABSTRACT: Summary: Cancer imparts an increased risk for venous thromboembolism (VTE). Direct mechanisms linking VTE with malignancy remain unknown. Our characterization of Doxorubicin (DOX)-resistant MCF7 breast cancer cells revealed links with antithrombotic pathways, as an anticoagulant transcriptional profile was observed. Specifically, the intracellular anticoagulant Tissue Factor Pathway Inhibitor 1 (TFPI1) protein was elevated and functional in all resistant models tested; TFPI1 accumulation coincided with reduced thrombin. TFPI1 overexpression in unselected cells elevated pro-malignant gene markers and increased DOX resistance. Furthermore, TFPI1 and Breast Cancer Resistant Protein (BCRP) levels increased early and remained sustained during selection. Finally, consistent with antithrombin-mediated hypoxic metastasis, Hypoxia-Inducible Factor 1 alpha (HIF1alpha) was elevated in drug resistant and TFPI1 overexpressing cells. Thus, increased TFPI1 may create an intratumoral hypoxic environment, potentially leading to drug resistance. MCF7 cells were selected for DOX resistance by first treating the cells with 1 microM DOX for 48 hours. The cells were then exposed to 100 nM DOX for 2 weeks. After this period, the surviving cells were resistant to further DOX treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Troy Harkness

PROVIDER: E-MTAB-1643 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response.

Davies Gerald F GF Berg Arnie A Postnikoff Spike D L SD Wilson Heather L HL Arnason Terra G TG Kusalik Anthony A Harkness Troy A A TA

PloS one 20140128 1

Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 breast cancer cells reveals a mechanism linking DOX exposure with hypoxic induction of DOX resistance. Global expression changes between parental and DOX resistant MCF7 cells were examined. Westerns, Northerns and immunocytochemistry were used to v ...[more]

PMID: 24489651

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Project description:The development of cytostatic-drug resistance renders chemotherapy ineffective in treating ovarian cancer, the most lethal gynaecological malignancy. In many cases, it is difficult to explain the development of drug resistance based on the expression patterns of genes known to be involved in this process. Microarray-based assays can provide information about new genes that are involved in the resistance to cytostatic drugs. This report describes alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. These drug-resistant variants of the W1 and A2780 cell lines were generated through the stepwise selection of cells tolerant of exposure to the indicated drugs at incrementally increased concentrations. Affymetrix GeneChip Human Genome Array Strips were used for hybridization assays. The genes with significantly altered expression levels (upregulated by more than fivefold or downregulated by less than fivefold relative to the level in the parental line) in the drug-resistant sublines were selected and were filtered using volcano plotting. We observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug. The level of expression of 13 genes was upregulated and that of nine genes was downregulated. In the CisPt-resistant cell line, we observed downregulated expression of ABCC6, BST2, ERAP2 and MCTP1; in the Pac-resistant cell line, we observe upregulated expression of ABCB1, EPHA7 and RUNDC3B and downregulated expression of LIPG, MCTP1, NSBP1, PCDH9, PTPRK and SEMA3A. The expression levels of three genes, ABCB1, ABCB4 and IFI16, were upregulated in the Dox-resistant cell lines. In the Top-resistant cell lines, we observed increased expression levels of ABCG2, HERC5, IFIH1, MYOT, S100A3, SAMD4A, SPP1 and TGFBI and decreased expression levels of MCTP1 and PTPRK

Dataset Information

Differential expression of genes involved in the transtion to Doxorubicin drug resistance in MCF7 breast cancer cells

Publications

TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response.

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