MicroRNAs and their target proteins are associated with characteristics of estrogen receptor-positive breast cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE38280 | GEO | 2013/03/04
SECONDARY ACCESSION(S): PRJNA167533
REPOSITORIES: GEO
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Project description:Recent analyses have identified heterogeneity in estrogen receptor (ER)-positive breast cancer. There are so-called luminal A and luminal B subtypes, and the characteristics, such as response to endocrine therapy and chemotherapy and prognosis, are different in these two subtypes of breast cancer. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissues were compared between highly and incompletely endocrine responsive tumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these two groups. We identified one miRNA that was downregulated in highly endocrine responsive tumors and 8 miRNAs that were downregulated in incompletely endocrine responsive tumors, and target genes of these miRNAs were predicted using TargetScan and MiRanda. Protein expression patterns of the predicted target genes and the genes that were identified by mRNA expression profiling were analyzed in ER-positive breast cancer samples by immunohistochemistry. We identified a novel protein that might be associated with characteristics of ER-positive breast cancer.
2013-03-04 | GSE38279 | GEO
Project description:Recent analyses have identified heterogeneity in estrogen receptor (ER)-positive breast cancer. There are so-called luminal A and luminal B subtypes, and the characteristics, such as response to endocrine therapy and chemotherapy and prognosis, are different in these two subtypes of breast cancer. In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissues were compared between highly and incompletely endocrine responsive tumors by miRNA and mRNA microarrays. Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs in these two groups. We identified one miRNA that was downregulated in highly endocrine responsive tumors and 8 miRNAs that were downregulated in incompletely endocrine responsive tumors, and target genes of these miRNAs were predicted using TargetScan and MiRanda. Protein expression patterns of the predicted target genes and the genes that were identified by mRNA expression profiling were analyzed in ER-positive breast cancer samples by immunohistochemistry. We identified a novel protein that might be associated with characteristics of ER-positive breast cancer.
2013-03-04 | GSE38278 | GEO
Project description:BackgroundRecent studies have shown that the regulatory effect of microRNAs can be investigated by examining expression changes of their target genes. Given this, it is useful to define an overall metric of regulatory effect for a specific microRNA and see how this changes across different conditions.ResultsHere, we define a regulatory effect score (RE-score) to measure the inhibitory effect of a microRNA in a sample, essentially the average difference in expression of its targets versus non-targets. Then we compare the RE-scores of various microRNAs between two breast cancer subtypes: estrogen receptor positive (ER+) and negative (ER-). We applied this approach to five microarray breast cancer datasets and found that the expression of target genes of most microRNAs was more repressed in ER- than ER+; that is, microRNAs appear to have higher RE-scores in ER- breast cancer. These results are robust to the microRNA target prediction method. To interpret these findings, we analyzed the level of microRNA expression in previous studies and found that higher microRNA expression was not always accompanied by higher inhibitory effects. However, several key microRNA processing genes, especially Ago2 and Dicer, were differentially expressed between ER- and ER+ breast cancer, which may explain the different regulatory effects of microRNAs in these two breast cancer subtypes.ConclusionsThe RE-score is a promising indicator to measure microRNAs' inhibitory effects. Most microRNAs exhibit higher RE-scores in ER- than in ER+ samples, suggesting that they have stronger inhibitory effects in ER- breast cancers.
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Project description:The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
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Project description:Obesity increases breast cancer mortality by promoting resistance to therapy. Here, we identified regulatory pathways in estrogen receptor-positive (ER-positive) tumors that were shared between patients with obesity and those with resistance to neoadjuvant aromatase inhibition. Among these was fibroblast growth factor receptor 1 (FGFR1), a known mediator of endocrine therapy resistance. In a preclinical model with patient-derived ER-positive tumors, diet-induced obesity promoted a similar gene expression signature and sustained the growth of FGFR1-overexpressing tumors after estrogen deprivation. Tumor FGFR1 phosphorylation was elevated with obesity and predicted a shorter disease-free and disease-specific survival for patients treated with tamoxifen. In both human and mouse mammary adipose tissue, FGF1 ligand expression was associated with metabolic dysfunction, weight gain, and adipocyte hypertrophy, implicating the impaired response to a positive energy balance in growth factor production within the tumor niche. In conjunction with these studies, we describe a potentially novel graft-competent model that can be used with patient-derived tissue to elucidate factors specific to extrinsic (host) and intrinsic (tumor) tissue that are critical for obesity-associated tumor promotion. Taken together, we demonstrate that obesity and excess energy establish a tumor environment with features of endocrine therapy resistance and identify a role for ligand-dependent FGFR1 signaling in obesity-associated breast cancer progression.
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Project description:BackgroundThe benefit of endocrine therapy for patients with estrogen receptor (ER)-low (1%-10%) positive breast cancer is a matter for debate. We aimed to compare the clinical characteristics and survival outcome of ER-low patients with ER-high (＞10%) positive patients and ER-negative patients.MethodsFrom the breast cancer database of our institution, we identified 5466 patients with known ER status who were diagnosed with early-stage breast cancer between January 2008 and December 2016. Variables associated with initiation of endocrine therapy were identified using multivariate logistic regression model. According to ER status, all patients were classified into ER-low (1%-10%), ER-high (>10%) and ER-negative subgroups. Fine and Gray competing risks regression was performed to compare the survival outcome of three subgroups.ResultsAge at diagnosis, ER status and progesterone receptor (PR) status were identified as correlates of initiation of endocrine therapy. ER-low patients were more likely to have advanced, PR-negative, human epidermal growth factor receptor 2 (HER2)-positive or grade Ⅲ disease compared to ER-high patients. Similar to ER-negative patients, ER-low patients presented increased rate of locoregional recurrence (LRR), distant recurrence (DR) and breast cancer mortality (BCM) than ER-high patients. Endocrine therapy showed nonsignificant trends toward lower LRR, DR and BCM in ER-low patients.ConclusionSimilar to ER-negative patients, ER-low patients had more aggressive clinical characteristics and worse survival outcome than ER-high patients. ER-low patients appeared to benefit less from endocrine therapy. Randomized studies are needed to further explore the endocrine responsiveness of ER-low patients.
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Project description:Background/aimEstrogen receptor α (ERα) antagonist is the most common treatment for ERα-positive breast cancer. However, compensatory signaling contributes to resistance to ERα antagonists. Thus, to explore the potential agents for targeting compensatory signaling, we screened multiple target inhibitors for breast cancer treatment.Materials and methodsWe attempted to build a structure-based virtual screening model that can find potential compounds and assay the anticancer ability of these drugs by overall cell survival assay. The downstream compensatory phosphorylated signaling was measured by immunoblotting.ResultsHamamelitannin and glucocheirolin were hits for ERα, phosphoinositide 3-kinase (PI3K), and KRAS proto-oncogene, GTPase (KRAS), which were active against estrogen and epidermal growth factor-triggered proliferation. Additionally, we select aminopterin as a hit for ERα, PI3K, KRAS, and SRC proto-oncogene, non-receptor tyrosine kinase (SRC) with inhibitory activities toward AKT serine/threonine kinase 1 (AKT) and mitogen-activated protein kinase kinase (MEK) signaling.ConclusionOur structure-based virtual screening model selected hamamelitannin, glucocheirolin, aminopterin, and pemetrexed as compounds that may act as potential inhibitors for improving endocrine therapies for breast cancer.
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