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Role of let-7 family microRNA in breast cancer.

ABSTRACT: Metastasis and resistance to therapy significantly contribute to cancer-related deaths. Growing body of evidence suggest that altered expression of microRNAs (miRNAs) is one of the root cause of adverse clinical outcome. miRNAs such as let-7 are the new fine tuners of signaling cascade and cellular processes which regulates the genes in post-transcriptional manner. In this review, we described the regulation of let-7 expression and the involvement of molecular factors in this process. We discussed the mechanism by which let-7 alter the expression of genes involved in the process of tumorigenesis. Further, we listed the pathways targeted by let-7 to reduce the burden of the tumor. In addition, we described the role of let-7 in breast cancer metastasis and stemness properties. This article will provide the in-depth insight into the biology of let-7 miRNA and its role in the breast cancer progression.

SUBMITTER: Thammaiah CK

PROVIDER: S-EPMC6096426 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Role of let-7 family microRNA in breast cancer.

Thammaiah Chadrashekar Kagepura CK Jayaram Shankar S

Non-coding RNA research 20161001 1

Metastasis and resistance to therapy significantly contribute to cancer-related deaths. Growing body of evidence suggest that altered expression of microRNAs (miRNAs) is one of the root cause of adverse clinical outcome. miRNAs such as let-7 are the new fine tuners of signaling cascade and cellular processes which regulates the genes in post-transcriptional manner. In this review, we described the regulation of let-7 expression and the involvement of molecular factors in this proce ...[more]

PMID: 30159414

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Project description:The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas. We analyzed by qRT-PCR the expression of miR-200f members and various EMT-transcriptional inducers in a series of 70 breast cancers comprising an array of phenotypic subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative (TN), including a subset of metaplastic breast carcinomas (MBCs) with sarcomatous (homologous or heterologous) differentiation. No MBCs with squamous differentiation were included. The DNA methylation status of miR-200f loci in tumor samples were inspected using Sequenom MassArray® MALDI-TOF platform. We also used two non-tumorigenic breast basal cell lines that spontaneously undergo EMT to study the modulation of miR-200f expression during EMT in vitro. We demonstrate that miR-200f is strongly decreased in MBCs compared with other cancer types. TN and HER2+ breast cancers also exhibited lower miR-200f expression than ER+ tumors. Significantly, the decreased miR-200f expression found in MBCs is accompanied by an increase in the expression levels of EMT-transcriptional inducers, and hypermethylation of the miR-200c-141 locus. Similar to tumor samples, we demonstrated that downregulation of miR-200f and hypermethylation of the miR-200c-141 locus, together with upregulation of EMT-transcriptional inducers also occur in an in vitro cellular model of spontaneous EMT. Thus, the expression and methylation status of miR-200f could be used as hypothetical biomarkers to assess the occurrence of EMT in breast cancer.

Project description:BackgroundThe study assessed the epigenetic regulation and the role of microRNA (miR) expression in locally advanced triple negative breast cancers (TNBC) and comparison with the clinico-pathological variables and survival.MethodsFifty patients of locally advanced TNBC during the period 2011-2013 were included. Expression level of test microRNA (miR-182 and miR-18a) was determined using Taqman quantitative Real time polymerase chain reaction (qRT-PCR) from formalin fixed paraffin embedded biopsy blocks. Clinical and demographic information and survival data was retrieved from the Hospital medical records.ResultsAn improved clinical complete response (cCR) was observed in patients with age ≥ 45 years (80%), premenopausal status (70%), tumor size < 6 cms (80%), nodal status N0-N1 (95%) and grade II-III tumor (80%). A statistically significant correlation was observed on comparison of cCR with menopausal status (p-value 0.020), T category (p-value 0.018) and the clinical nodal status (p-value 0.003). pCR also correlated with clinical nodal status (p-value 0.008). Epigenetically, miR-18a under expression (< 8.84) was most commonly associated with tumor size < 6 cms (76.7%), clinical nodal status N0-N1 (90%), cCR (60%) and pCR (53.3%). A similar trend was observed with miR-182. Statistical significance was observed with T category (p-values 0.003 and 0.004), clinical nodal status (p-values 0.001 and 0.001), clinical response (p-values 0.002 and 0.002) and pathological response (p-values 0.007 and 0.006) with respect to miR-18a and miR-182, respectively. Also, the menopausal status significantly correlated with the miR-182 expression (p-value 0.009). miR-182 overexpression (≥ 6.32) was not observed in any of the postmenopausal patients. A univariate cox proportional hazard regression model also showed statistical interactions (p-values <0.004).ConclusionmiR-182 and miR-18a overexpression correlates with worse clinical and pathological tumor characteristics in locally advanced TNBC and hence could be used to predict the outcomes and prognosis in these patients.

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Role of let-7 family microRNA in breast cancer.

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Role of <i>let-7</i> family microRNA in breast cancer.

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