Let-7a/cMyc/CCAT-1/miR-17-5p Circuit Modulates PDL-1 Expression and Atezolizumab Resistance in Triple Negative Breast Cancer (original) (raw)
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Oncology Letters
Long non-coding RNAs (lncRNAs) have attracted widespread attention as potential biological and pathological regulators. lncRNAs are involved in several biological processes in cancer. Triple negative breast cancer (TNBC) is characterized by strong heterogeneity and aggressiveness. At present, the implication of microRNAs (miRs) and lncRNAs in immunotherapy has been poorly studied. Nevertheless, the blockade of immune checkpoints, particularly that of the programmed cell-death protein-1/programmed cell-death ligand-1 (PD-L1) axis, is considered as a principle approach in breast cancer (BC) therapy. The present study aimed to investigate the interaction between immune-modulatory upstream signaling pathways of the PD-L1 transcript that could enhance personalized targeted therapy. MDA-MB-231 cells were transfected with miR-182-5p mimics followed by RNA extraction and cDNA synthesis using a reverse transcription kit, and the expression levels of the target genes were assessed by reverse transcription-quantitative PCR. Furthermore, the expression levels of target genes were measured in tissues derived from 41 patients with BC, including patients with luminal BC and TNBC, as well as their adjacent lymph nodes. The results revealed that the expression levels of miR-182-5p, PD-L1 and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were upregulated in MDA-MB-231 cells and BC tissues. However, X-inactive specific transcript (XIST) expression was downregulated in cancer tissues and TNBC cells. Following co-transfection of cells with small interfering RNAs specific for each target gene and miR-182-5p antagomirs, the effect of miR-182-5p was abolished in the presence of lncRNAs. Therefore, the results of the present study indicated that although miR-182-5p exhibited an oncogenic effect, XIST exerted a dominant effect on the regulation of the PD-L1 signaling pathway via the inhibition of the oncogenic function of MALAT1.
Clinical Epigenetics, 2018
Triple-negative breast cancer (TNBC) has been clinically difficult to manage because of tumor aggressiveness, cellular and histological heterogeneity, and molecular mechanisms' complexity. All this in turn leads us to evaluate that tumor biological behavior is not yet fully understood. Additionally, the heterogeneity of tumor cells represents a great biomedicine challenge in terms of the complex molecular-genetical-transcriptional and epigenetical-mechanisms, which have not been fully elucidated on human solid tumors. Recently, human breast cancer, but specifically TNBC is under basic and clinical-oncology research in the discovery of new molecular biomarkers and/or therapeutic targets to improve treatment responses, as well as for seeking algorithms for patient stratification, seeking a positive impact in clinical-oncology outcomes and life quality on breast cancer patients. In this sense, important knowledge is emerging regarding several cancer molecular aberrations, including higher genetic mutational rates, LOH, CNV, chromosomal, and epigenetic alterations, as well as transcriptome aberrations in terms of the total gene-coding ribonucleic acids (RNAs), known as mRNAs, as well as non-coding RNA (ncRNA) sequences. In this regard, novel investigation fields have included microRNAs (miRNAs), as well as long ncRNAs (lncRNAs), which have been importantly related and are likely involved in the induction, promotion, progression, and/ or clinical therapeutic response trackers of TNBC. Based on this, in general terms according with the five functional archetype classification, the lncRNAs may be involved in the regulation of several molecular mechanisms which include genetic expression, epigenetic, transcriptional, and/or post-transcriptional mechanisms, which are nowadays not totally understood. Here, we have reviewed the main dis-regulated and functionally non-and well-characterized lncRNAs and their likely involvement, from a molecular enrichment and mechanistic point of view, as tumor biomarkers for breast cancer and its specific histological subtype, TNBC. In reference to the abovementioned, it has been described that some lncRNA expression profiles correspond or are associated with the TNBC histological subtype, potentially granting their use for TNBC malignant progression, diagnosis, tumor clinical stage, and likely therapy. Based on this, lncRNAs have been proposed as potential biomarkers which might represent potential predictive tools in the differentiated breast carcinomas versus TNBC malignant disease. Finally, elucidation of the specific or multi-functional archetypal of lncRNAs in breast cancer and TNBC could be fundamental, as these molecular intermediary-regulator "lncRNAs" are widely involved in the
PLOS ONE, 2020
Background Long non-coding RNAs (lncRNAs) are characterized as having 200 nucleotides or more and not coding any protein, and several been identified as differentially expressed in several human malignancies, including breast cancer. Methods Here, we evaluated lncRNAs differentially expressed in triple-negative breast cancer (TNBC) from a cDNA microarray data set obtained in a previous study from our group. Using in silico analyses in combination with a review of the current literature, we identify three lncRNAs as potential prognostic factors for TNBC patients. Results We found that the expression of WDFY3-AS2, BDNF-AS, and AFAP1-AS1 was associated with poor survival in patients with TNBCs. WDFY3-AS2 and BDNF-AS are lncRNAs known to play an important role in tumor suppression of different types of cancer, while AFAP1-AS1 exerts oncogenic activity. Conclusion Our findings provided evidence that WDFY3-AS2, BDNF-AS, and AFAP1-AS1 may be potential prognostic factors in TNBC development.
Breast cancer is a complex and diverse condition that disrupts multiple signaling pathways essential for cell proliferation, survival, and differentiation. Recently, the significant involvement of long-chain non-coding RNAs (lncRNAs) in controlling key signaling pathways associated with breast cancer development has been discovered. This review aims to explore the interaction between lncRNAs and various pathways, including the AKT/PI3K/ mTOR, Wnt/β-catenin, Notch, DNA damage response, TGF-β, Hedgehog, and NF-κB signaling pathways, to gain a comprehensive understanding of their roles in breast cancer. The AKT/PI3K/mTOR pathway regulates cell growth, survival, and metabolic function. Recent data suggests that specific lncRNAs can influence the functioning of this pathway, acting as either oncogenes or tumor suppressors. Dysregulation of this pathway is commonly observed in breast cancer cases. Moreover, breast cancer development has been associated with other pathways such as Wnt/β-catenin, Notch, TGF-β, Hedgehog, and NF-κB. Emerging studies have identified lncRNAs that modulate breast cancer's growth, progression, and metastasis by interacting with these pathways. To advance the development of innovative diagnostic tools and targeted treatment options, it is crucial to comprehend the intricate relationship between lncRNAs and vital signaling pathways in breast cancer. By fully harnessing the therapeutic potential of lncRNAs, there is a possibility of developing more effective and personalized therapy choices for breast cancer patients. Further investigation is necessary to comprehensively understand the role of lncRNAs within breast cancer signaling pathways and fully exploit their therapeutic potential.
International Journal of Molecular Sciences, 2021
Breast cancer (BC) is the most frequent malignancy identified in adult females, resulting in enormous financial losses worldwide. Owing to the heterogeneity as well as various molecular subtypes, the molecular pathways underlying carcinogenesis in various forms of BC are distinct. Therefore, the advancement of alternative therapy is required to combat the ailment. Recent analyses propose that long non-coding RNAs (lncRNAs) perform an essential function in controlling immune response, and therefore, may provide essential information about the disorder. However, their function in patients with triple-negative BC (TNBC) has not been explored in detail. Here, we analyzed the changes in the genomic expression of messenger RNA (mRNA) and lncRNA in standard control in response to cancer metastasis using publicly available single-cell RNA-Seq data. We identified a total of 197 potentially novel lncRNAs in TNBC patients of which 86 were differentially upregulated and 111 were differentially ...
Cells, 2020
Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.
The lncRNA BORG facilitates the survival and chemoresistance of triple-negative breast cancers
Oncogene, 2018
Disseminated breast cancer cells employ adaptive molecular responses following cytotoxic therapeutic insult which promotes their survival and subsequent outgrowth. Here we demonstrate that expression of the pro-metastatic lncRNA BORG (BMP/OP-Responsive Gene) is greatly induced within triple-negative breast cancer (TNBC) cells subjected to environmental and chemotherapeutic stresses commonly faced by TNBC cells throughout the metastatic cascade. This stress-mediated induction of BORG expression fosters the survival of TNBC cells and renders them resistant to the cytotoxic effects of doxorubicin both in vitro and in vivo. The chemoresistant traits of BORG depend upon its robust activation of the NF-κB signaling axis via a novel BORG-mediated feed-forward signaling loop, and via its ability to bind and activate RPA1. Indeed, genetic and pharmacologic inhibition of NF-κB signaling or the DNA-binding activity of RPA1 abrogates the pro-survival features of BORG and renders BORG-expressing TNBCs sensitive to doxorubicin-induced cytotoxicity. These findings suggest that therapeutic targeting of BORG or its downstream molecular effectors may provide a novel means to alleviate TNBC recurrence.
Genes
The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various in...