The Impact of HER2 Overexpression on the miRNA and circRNA Transcriptomes in Two Breast Cell Lines and Their Vesicles

Amorim, María Galli de; Branco, Gabriela P.; Valieris, Renan; Tarcitano, Emilio; Silva, Israel Tojal da; Araújo, Luíza Ferreira de; Nunes, Diana Noronha; Dias‐Neto, Emmanuel

doi:10.2217/pgs-2018-0182

Cited by 7 publications

(8 citation statements)

References 48 publications

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“…Three of them (miR-30d-5p, miR-195-5p, and miR-223-3p) were previously reported to be downregulated in HER2-overexpressing/amplified cancers [22][23][24]. miR-223-3p is also downregulated in HER2-overexpressing C5.2 cell line [25]. Citron et al postulated a central role for miR-223 in the control of epidermal growth factor signaling and HER2 activation, as it reduces the oncogenic potential of HER2-transformed mammary epithelial cells [26].…”

Section: Discussionmentioning

confidence: 94%

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

et al. 2020

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Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student’s T-test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(−)/PgR(+) and ER(+)/PgR(−) breast cancers. However, a trend for differing expression (p-value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(−) group demonstrated elevated levels of four miRNAs—miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p—while the ER(−)/PgR(+) tumors were enriched in another four miRNAs—miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs—miR-29c-3p—the association with the ER(+)/PgR(−) phenotype was confirmed in the TCGA cohort (p-value = 0.024; T-test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(−) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(−)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(−)/PgR(+) and ER(+)/PgR(−) tumors.

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Section: Discussionmentioning

confidence: 94%

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

et al. 2020

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“…Presence of growth factors leads to heterodimerization and activation of MAPK and PI3K signaling pathways (Graus-Porta et al, 1997). ERBB2 is a proto-oncogene that is overexpressed in approximately 25% of breast cancers, but also in gastric and other cancers, leading to malignant transformation of epithelial cells (Slamon et al, 2011;Fang et al, 2017;Galli de Amorim et al, 2019). Overexpression occurs mostly due to gene amplification, but other activating mutations were also described (Slamon et al, 2011;Galli de Amorim et al, 2019).…”

Section: Erbb2mentioning

confidence: 99%

“…ERBB2 is a proto-oncogene that is overexpressed in approximately 25% of breast cancers, but also in gastric and other cancers, leading to malignant transformation of epithelial cells (Slamon et al, 2011;Fang et al, 2017;Galli de Amorim et al, 2019). Overexpression occurs mostly due to gene amplification, but other activating mutations were also described (Slamon et al, 2011;Galli de Amorim et al, 2019). ERBB2 overexpression is associated with a more aggressive phenotype with worse survival because of increased proliferation, invasiveness and metastasis (Slamon et al, 2011).…”

Section: Erbb2mentioning

confidence: 99%

“…Introduction of targeted treatment significantly improved response and survival in HER2-positive breast cancer patients (Slamon et al, 2011). However, not all patients respond to treatment with trastuzumab and some patients develop resistance, therefore additional biomarkers are needed to further improve treatment outcome (Ciravolo et al, 2012;Galli de Amorim et al, 2019). ERBB2 was frequently identified in EVs (Table 1).…”

Section: Erbb2mentioning

confidence: 99%

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Extracellular Vesicles: A Novel Tool Facilitating Personalized Medicine and Pharmacogenomics in Oncology

2021

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Biomarkers that can guide cancer therapy based on patients’ individual cancer molecular signature can enable a more effective treatment with fewer adverse events. Data on actionable somatic mutations and germline genetic variants, studied by personalized medicine and pharmacogenomics, can be obtained from tumor tissue or blood samples. As tissue biopsy cannot reflect the heterogeneity of the tumor or its temporal changes, liquid biopsy is a promising alternative approach. In recent years, extracellular vesicles (EVs) have emerged as a potential source of biomarkers in liquid biopsy. EVs are a heterogeneous population of membrane bound particles, which are released from all cells and accumulate into body fluids. They contain various proteins, lipids, nucleic acids (miRNA, mRNA, and DNA) and metabolites. In cancer, EV biomolecular composition and concentration are changed. Tumor EVs can promote the remodeling of the tumor microenvironment and pre-metastatic niche formation, and contribute to transfer of oncogenic potential or drug resistance during chemotherapy. This makes them a promising source of minimally invasive biomarkers. A limited number of clinical studies investigated EVs to monitor cancer progression, tumor evolution or drug resistance and several putative EV-bound protein and RNA biomarkers were identified. This review is focused on EVs as novel biomarker source for personalized medicine and pharmacogenomics in oncology. As several pharmacogenes and genes associated with targeted therapy, chemotherapy or hormonal therapy were already detected in EVs, they might be used for fine-tuning personalized cancer treatment.

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“…Predicted potential circRNA-miRNA interaction networks showed that hsa-circRNA-0088088 and hsa-circRNA-0005795 might function as ceRNAs and were associated with several cancer-related pathways, such as the Wnt, estrogen, TGF-b, and FoxO signaling pathways (58). Amorim et al presented a nextgeneration sequencing (NGS)-based transcriptome view of the miRNA and circRNA landscape of two breast-derived cell lines, HB4a and C5.2, in the context of HER2 upregulation, demonstrating that identification of hundreds of circRNAs in these cells as well as their exosome-containing EVs (59). Wang identified 5842 DE circRNAs in the MDA-MB-231 cells compared with the MCF-7 cells by cluster analysis (60).…”

Section: Exosomal Circrnasmentioning

confidence: 99%

Tumor-Derived Exosomal Non-Coding RNAs: The Emerging Mechanisms and Potential Clinical Applications in Breast Cancer

Zeng

et al. 2021

Front. Oncol.

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Breast cancer (BC) is the most frequent malignancy and is ranking the leading cause of cancer-related death among women worldwide. At present, BC is still an intricate challenge confronted with high invasion, metastasis, drug resistance, and recurrence rate. Exosomes are membrane-enclosed extracellular vesicles with the lipid bilayer and recently have been confirmed as significant mediators of tumor cells to communicate with surrounding cells in the tumor microenvironment. As very important orchestrators, non-coding RNAs (ncRNAs) are aberrantly expressed and participate in regulating gene expression in multiple human cancers, while the most reported ncRNAs within exosomes in BC are microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Notably, ncRNAs containing exosomes are novel frontiers to shape malignant behaviors in recipient BC cells such as angiogenesis, immunoregulation, proliferation, and migration. It means that tumor-derived ncRNAs-containing exosomes are pluripotent carriers with intriguing and elaborate roles in BC progression via complex mechanisms. The ncRNAs in exosomes are usually excavated based on specific de-regulated expression verified by RNA sequencing, bioinformatic analyses, and PCR experiments. Here, this article will elucidate the recent existing research on the functions and mechanisms of tumor-derived exosomal miRNA, lncRNA, circRNA in BC, especially in BC cell proliferation, metastasis, immunoregulation, and drug resistance. Moreover, these tumor-derived exosomal ncRNAs that existed in blood samples are proved to be excellent diagnostic biomarkers for improving diagnosis and prognosis. The in-depth understanding of tumor-derived exosomal ncRNAs in BC will provide further insights for elucidating the BC oncogenesis and progress and exploring novel therapeutic strategies for combating BC.

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The Impact of HER2 Overexpression on the miRNA and circRNA Transcriptomes in Two Breast Cell Lines and Their Vesicles

Cited by 7 publications

References 48 publications

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study

Extracellular Vesicles: A Novel Tool Facilitating Personalized Medicine and Pharmacogenomics in Oncology

Tumor-Derived Exosomal Non-Coding RNAs: The Emerging Mechanisms and Potential Clinical Applications in Breast Cancer

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