Transcription profiling by array of aromatase-inhibitor-resistant breast cancer cell lines derived from T-47D to identify the genes related to aromatase-inhibitor-resistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Fujii Rika
PROVIDER: S-ECPF-MTAB-1933 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:To identify the genes which have relation to aromatase-inhibitor-resistance, we compared the gene expression of aromatase-inhibitor-resistant cell, A3, with that of parent cell line, T-47D.
2014-04-01 | E-MTAB-1933 | biostudies-arrayexpress
Project description:Understanding the complex molecular mechanisms underlying resistance to endocrine therapy is a major challenge in the treatment of estrogen receptor-positive (ER+) breast cancers. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) signaling via the receptor tyrosine kinase RET promotes estrogen independent activation of ER. Here we have addressed the relevance of GDNF-RET signaling in response to aromatase inhibitor treatment and explored the efficacy of using RET inhibitors in breast cancer models of aromatase inhibitor response and resistance. A GDNF-response gene set, identified from gene expression profiling, was demonstrated to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to aromatase inhibitor treatment and development of resistance. The relevance of these findings was validated first by demonstrating an association of RET protein expression in an independent cohort of aromatase inhibitor resistant patient samples. Second, in in vitro models, GDNF-mediated RET signaling was demonstrated to enhance the survival of aromatase inhibitor resistant cells and to increase resistance in aromatase inhibitor sensitive cells. These effects could be reversed by targeting GDNF/RET signaling with the RET selective inhibitor NVP-BBT594 thus identifying GDNF-RET signaling as a potential therapeutic target, particularly in breast cancers resistant to aromatase inhibitors.MCF7 cells were E2-deprived by culturing in phenol red-free RPMI 1640 supplemented with 10% DCC for 3 days and then serum-starved overnight in the presence or absence of fulvestrant (ICI182,780) (100 nM). The following day, cells were treated with GDNF (20 ng/ml) for 0, 4, 8, 24 and 48 hours in the presence or absence of fulvestrant (ICI182,780) (100 nM).
| S-ECPF-MEXP-3662 | biostudies-other
Project description:We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy.
| S-EPMC5940386 | biostudies-other
Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3’UTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance. To look at microRNA expression profiles of breast cancer cell lines derived from MCF-7 cells that are resistant to endocrine therapy agents. MCF-7 cells that overexpress aromatase (MCF-7aro) were cultured long-term in the presence of endocrine therapy agents until cells acquired resistance. Three different aromatase inhibitors (letrozole, anastrozole or exemestane) were used, as well as the ER antagonist tamoxifen, or the hormone-free long-term estrogen deprived cells (LTED). Three replicates of the control cells (MCF-7aro) and all resistant cells were used for microarray experiments. Total of 23 samples were analyzed by microarray.
| S-ECPF-GEOD-17775 | biostudies-other
Project description:MCF-7aro cells were used to generate a cell culture model system that is resistant to 3 aromatase inhibitors (AIs), letrozole, anastrozole and exemestane. For comparison, the MCF-7aro cells were also used to generate the tamoxifen-resistant cells as well as long-term estrogen deprived, LTEDaro. Affymetrix microarray analysis was performed to determine changes in gene expression that are unique to AI-resistance. Experiment Overall Design: For control purposes, MCF-7aro cells were cultured without any hormone or inhibitor as well as a hormone-only control (T-only). Resistant cells were grown in the presence of testosterone, T+LET R (letrozole), T+ANA R (anastrozole), T+EXE R (exemestane), T+TAM R (Tamoxifen). In addition, testosterone-free resistant lines were generated, LTEDaro, ANA R and EXE R. 6 replicates were generated for the hormone-containing resistant lines and 3 replicates for the hormone-free resistant lines.
2008-04-04 | E-GEOD-10911 | biostudies-arrayexpress
Project description:MCF-7aro cells were used to generate a cell culture model system that is resistant to 3 aromatase inhibitors (AIs), letrozole, anastrozole and exemestane. For comparison, the MCF-7aro cells were also used to generate the tamoxifen-resistant cells as well as long-term estrogen deprived, LTEDaro. Affymetrix microarray analysis was performed to determine changes in gene expression that are unique to AI-resistance. Keywords: cell lines, aromatase inhibitor resistance, tamoxifen resistance
2008-03-22 | GSE10911 | GEO
Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3’UTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance.
2010-01-01 | GSE17775 | GEO
Project description:Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.
| S-EPMC3496110 | biostudies-literature
Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3âUTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance. To look at microRNA expression profiles of breast cancer cell lines derived from MCF-7 cells that are resistant to endocrine therapy agents. MCF-7 cells that overexpress aromatase (MCF-7aro) were cultured long-term in the presence of endocrine therapy agents until cells acquired resistance. Three different aromatase inhibitors (letrozole, anastrozole or exemestane) were used, as well as the ER antagonist tamoxifen, or the hormone-free long-term estrogen deprived cells (LTED). Three replicates of the control cells (MCF-7aro) and all resistant cells were used for microarray experiments. Total of 23 samples were analyzed by microarray.
2010-05-16 | E-GEOD-17775 | biostudies-arrayexpress
Project description:BackgroundThe tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR).MethodsMCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 μg/day), tamoxifen (500 μg/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant.ResultsIn the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ERα target genes, Ki67 and Akt expression in vivo.ConclusionIn endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.
| S-EPMC7238733 | biostudies-literature