A long noncoding RNA landscape in breast cancer reveals a potential role for lncRNA AC009283.1 in proliferation and apoptosis in HER2-enriched molecular subtype
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PROVIDER: PRJNA554575 | ENA |
REPOSITORIES: ENA
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Project description:We silenced lncRNA AC009283.1 using shRNAs in cell line SKBR3, carried a ~75% silencing compared to thenegative control (NC). We evaluated the role of lncRNA AC009283.1 on oncogenic phenotypes in the HER2-enriched SKBR3 breast cancer cell line model. The knockdown of lncRNA AC009283.1 was achieved with ~75% of silencing efficiency. A complete transcriptomic analysis after silencing of lncRNA AC009283.1 revealed an impact on the global expression.
2020-08-12 | GSE134254 | GEO
Project description:Breast cancer is the most commonly diagnosed neoplasm in women worldwide with a well-recognized heterogeneous pathology, classified into four molecular subtypes: Luminal A, Luminal B, HER2-enriched and Basal-like, each one with different biological and clinical characteristics. Long non-coding RNAs (lncRNAs) represent 33% of the human transcriptome and play critical roles in breast carcinogenesis, but most of their functions are still unknown. Therefore, cancer research could benefit from continued exploration into the biology of lncRNAs in this neoplasm. We characterized lncRNA expression portraits in 74 breast tumors belonging to the four molecular subtypes using transcriptome microarrays. To infer the biological role of the deregulated lncRNAs in the molecular subtypes, we performed co-expression analysis of lncRNA-mRNA and gene ontology analysis. We identified 307 deregulated lncRNAs in tumor compared to normal tissue and 354 deregulated lncRNAs among the different molecular subtypes. Through co-expression analysis between lncRNAs and protein-coding genes, along with gene enrichment analysis, we inferred the potential function of the most deregulated lncRNAs in each molecular subtype, and independently validated our results taking advantage of TCGA data. Overexpression of the AC009283.1 was observed in the HER2-enriched subtype and it is localized in an amplification zone at chromosome 17q12, suggesting it to be a potential tumorigenic lncRNA. The functional role of lncRNA AC009283.1 was examined through loss of function assays in vitro and determining its impact on global gene expression. These studies revealed that AC009283.1 regulates genes involved in proliferation, cell cycle and apoptosis in a HER2 cellular model. We further confirmed these findings through ssGSEA and CEMITool analysis in an independent HER2-amplified breast cancer cohort. Our findings suggest a wide range of biological functions for lncRNAs in each breast cancer molecular subtype and provide a basis for their biological and functional study, as was conducted for AC009283.1, showing it to be a potential regulator of proliferation and apoptosis in the HER2-enriched subtype.
| S-EPMC7403317 | biostudies-literature
Project description:1. Evaluate the diagnostic value of long noncoding RNA (CCAT1) expression by RT-PCR in peripheral blood in colorectal cancer patients versus normal healthy control personal.
2. Evaluate the clinical utility of detecting long noncoding RNA (CCAT1) expression in diagnosis of colorectal cancer patients & its relation to tumor staging.
3. Evaluate the clinical utility of detecting long noncoding RNA (CCAT1) expression in precancerous colorectal diseases.
4. Compare long noncoding RNA (CCAT1) expression with traditional marker; carcinoembryonic antigen (CEA) and Carbohydrate antigen 19-9 (CA19-9) in diagnosis of colorectal cancer.
| 2330122 | ecrin-mdr-crc
Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors.
2012-05-12 | GSE37946 | GEO
Project description:We identified a 17-gene Her2-enriched tumor initiating cell (HTIC) signature in MMTV-Her2/Neu mouse mammary TICs. Here, we show that patients with HTICS+ HER2+:ERα− tumors are more likely to achieve a pathologic complete response to trastuzumab-based neoadjuvant chemotherapy compared with HER2+:ER+ tumors. Neoadjuvant study of 50 HER2-positive breast cancer cases treated with trastuzumab-based chemotherapy pre-operatively. Pre-treatment FNA from primary tumors were obtained and RNA extracted and hybridized to Affymetrix microarrays according to manufacturer protocol. Pathologic response was assessed at the end of neoadjuvant treatment.
2012-05-11 | E-GEOD-37946 | biostudies-arrayexpress
Project description:HER2 (ERBB2) gene amplification and PIK3CA mutations often co-occur in breast cancer, and aberrant activation of the PI3K pathway has been implicated in resistance to HER2-directed therapies. We have created a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in their mammary glands developed tumors with a significantly shorter latency compared to mice expressing either oncogene alone. By microarray analysis, HER2-driven tumors clustered with the luminal subtype, whereas HER2+PIK3CA and PIK3CA-driven tumors were associated with the claudin-low breast cancer subtype. In accordance, PIK3CA and HER2+PIK3CA tumors expressed elevated levels of EMT and stem cell markers, and cells from HER2+PIK3CA tumors more efficiently formed mammospheres, providing further evidence that activated PIK3CA may enrich for cancer stem cells. Finally, HER2+PIK3CA tumors are resistant to the HER2 antibody trastuzumab; resistance is partially reversed by the addition of a PI3K inhibitor. Taken together, these studies suggest that the co-expression of HER2 and PI3KH1047R in the mouse mammary gland accelerates the formation of aggressive, trastuzumab-resistant tumors. referenceXsample
2013-09-03 | E-GEOD-41118 | biostudies-arrayexpress
Project description:BackgroundIdentification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.MethodsA research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.ResultsA total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).ConclusionsCombining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
| S-EPMC7850037 | biostudies-literature
Project description:In the normal breast, PMCA2 transports calcium into milk. It is also upregulated in breast cancer cells and high tumor levels predict increased mortality in patients. In this study, we examined interactions between PMCA2 and HER2. We find that PMCA2 and a scaffolding protein, NHERF1, interact together with HER2 in specific membrane domains protruding from the surface of breast cancer cells. Knocking down PMCA2 or NHERF1 increases intracellular calcium and leads to the ubiquitination, endocytosis and degradation of HER2 after receptor activation. This is associated with reductions in HER2 expression and signaling. Manipulating PMCA2 levels regulates proliferation and apoptosis of breast cancer cells in vitro and knocking out PMCA2 dramatically inhibits the formation of hyperplasia and tumors in MMTV-Neu mice. Gene expression profiling was performed on control SKBR3 cells vs. PMCA2, NHERFR1 and HER2 knock down cells. Each group has 6 duplicates.
2014-10-22 | E-GEOD-62555 | biostudies-arrayexpress
Project description:HER2 (ERBB2) gene amplification and PIK3CA mutations often co-occur in breast cancer, and aberrant activation of the PI3K pathway has been implicated in resistance to HER2-directed therapies. We have created a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in their mammary glands developed tumors with a significantly shorter latency compared to mice expressing either oncogene alone. By microarray analysis, HER2-driven tumors clustered with the luminal subtype, whereas HER2+PIK3CA and PIK3CA-driven tumors were associated with the claudin-low breast cancer subtype. In accordance, PIK3CA and HER2+PIK3CA tumors expressed elevated levels of EMT and stem cell markers, and cells from HER2+PIK3CA tumors more efficiently formed mammospheres, providing further evidence that activated PIK3CA may enrich for cancer stem cells. Finally, HER2+PIK3CA tumors are resistant to the HER2 antibody trastuzumab; resistance is partially reversed by the addition of a PI3K inhibitor. Taken together, these studies suggest that the co-expression of HER2 and PI3KH1047R in the mouse mammary gland accelerates the formation of aggressive, trastuzumab-resistant tumors.
2013-09-03 | GSE41118 | GEO
Project description:Purpose In breast cancer, specific aberrant methylation patterns have been associated with different BC histologic and molecular subtypes and data suggest that DNA methylation profiles may play an important role in the development and progression of distinct breast subtypes. However, the epigenome of the newly defined luminal B and luminal B-HER2 positive breast cancers has not yet been characterized. Therefore the main goal of the current study is to deciphered the aberrant DNA methylation profiles associated with these breast cancer subtypes. Experimental Design 29 luminal subtype breast cancer samples along with 8 control tissue were epigenetically interrogated using the HumanMethylation27 DNA Analysis BeadChip. Results Luminal B-HER2 + subtype displays the most aggressive phenotype and shows the highest number of aberrantly methylated CpG markers. On the other hand, the luminal B subtype harbours an heterogeneous DNA methylation profile that seems to be half way between the luminal A and luminalB-HER2+ subtypes. Conclusions The heterogeneous epigenetic and genetic profile of the luminal B subtype, might indicate that a further stratification has to be done for this specific breast cancer subtype.
2016-12-18 | GSE73808 | GEO