Circulating miR-200c and miR-141 and outcomes in patients with breast cancerby Silvia Antolín, Lourdes Calvo, Moisés Blanco-Calvo, María Paz Santiago, María José Lorenzo-Patiño, Mar Haz-Conde, Isabel Santamarina, Angélica Figueroa, Luis Miguel Antón-Aparicio, Manuel Valladares-Ayerbes

BMC Cancer

About

Year
2015
DOI
10.1186/s12885-015-1238-5
Subject
Oncology / Cancer Research / Genetics

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RESEARCH ARTICLE

Circulating miR-200c and in patients with breast can ría , L o e proved steadily in all developed countries over the past of specific biomarkers characterizing the metastatic

Antolín et al. BMC Cancer (2015) 15:297

DOI 10.1186/s12885-015-1238-5bryonic antigen, CA 15.3 and CA 27.59 could provideCarretera del Pasaje, s/n. PC 15006, La Coruña, Spain

Full list of author information is available at the end of the article25 years. By (2012), it was estimated that Spain would have a total of 27,000 new diagnoses of BC among women and currently BC remains the leading cause of death among women in Spain with 6231 deaths and a phenotype holds the promises of personalised therapy and improved prognosis prediction in many neoplastic diseases including BC.

Tumour tissue based biomarkers (e.g. size, grade, node status, hormone receptor status, HER2, Ki-67) are widely used in the clinical practice in BC. In addition, gene expression signatures of breast carcinomas have led to new classifications of tumour subgroups and also carry prognostic and predictive information [3]. In contrast, although serum tumour markers, including carcinoem* Correspondence: Manuel.Valladares.Ayerbes@sergas.es 1Medical Oncology Department, La Coruña University Hospital (CHUAC),

Servicio Galego de Saúde (SERGAS), As Xubias, 84 PC 15006, La Coruña,

Spain 2Translational Cancer Research Lab, Biomedical Research Institute (INIBIC),2008 [1]. Relative survival from BC in women has im-the whole blood can identify breast cancer (BC), and could be developed into a prognostic signature.

Methods: The expression of miR-200c and miR-141 were examined in bloods (57 stage I-IV BC patients and 20 age-matched controls) by quantitative reverse-transcription PCR. The associations of circulating microRNAs with clinic and pathological characteristics were analysed. Their effects on survival were analysed by the Kaplan-Meier method and Cox regressions.

Results: MiR-200c was down regulated (P < 0.0001) in the blood of BC patients, yielded an area under the ROC curve of 0.79 (90% sensitivity, 70.2% specificity) in discriminating BC from controls. Circulating miR-141 was not discriminating. MiR-200c and miR-141 in the blood of BC patients were inversely correlated (P = 0.019). The miR-200c levels were numerically higher in stage IV and tumours with lower MIB-1. MiR-141 was significantly higher in the blood of patients with stage I-III, lymph node metastasis, and HER2 negative tumours. High blood expression of miR-200c and/or low expression of miR-141 was associated with unfavourable overall survival (hazard ratio, 3.89; [95% CI: 1.28-11.85]) and progression-free survival (3.79 [1.41–10.16]) independent of age, stage and hormonal receptors.

Conclusions: Circulating miR-200c and miR-141 were deregulated in BC comparing with controls. Furthermore, miR-200c and miR-141 were independent prognostic factors and associated with distinct outcomes of BC patients.

Keywords: Breast neoplasm, microRNAs, Blood, Biomarkers, Prognostic factors

Background

Breast cancer (BC) is the leading cause of cancer death in women worldwide, accounting for 458,400 deaths in

European age-standardised mortality rate of 18 per 100,000 person-years [2].

Cancer progression and blood-borne metastasis contribute to the great majority of BC deaths. The discoverySilvia Antolín1, Lourdes Calvo1, Moisés Blanco-Calvo2, Ma

Mar Haz-Conde2, Isabel Santamarina2, Angélica Figueroa2 and Manuel Valladares-Ayerbes1,2*

Abstract

Background: The deregulation of microRNAs in both tum indicate the presence of cancer and predict prognosis. W© 2015 Antolín et al.; licensee BioMed Central

Commons Attribution License (http://creativec reproduction in any medium, provided the or

Dedication waiver (http://creativecommons.or unless otherwise stated.Open Access miR-141 and outcomes cer

Paz Santiago3, María José Lorenzo-Patiño3, uis Miguel Antón-Aparicio1,4 urs and blood has led to the search for microRNAs to hypothesize the deregulation of miR-200c/miR-141 in. This is an Open Access article distributed under the terms of the Creative ommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and iginal work is properly credited. The Creative Commons Public Domain g/publicdomain/zero/1.0/) applies to the data made available in this article,

Antolín et al. BMC Cancer (2015) 15:297 Page 2 of 15some prognostic information, they are not currently recommended for screening, diagnosis, or routine surveillance after initial treatment [4].

A large amount of data has revealed the correlation between specific tumours and differential microRNA (miRNA) expression profiles, thus providing a new class of disease-specific biomarkers (revised in [5]). MiRNAs are 18- to 25-nt noncoding RNA molecules that regulate protein expression of specific mRNA by either translational inhibition or mRNAs degradation. MiRNAs play different regulatory roles in cancer and have distinct functions in controlling the cell cycle, proliferation, invasion and metastasis. Moreover, miRNA deregulation can induce a pro-inflammatory and pro-metastatic environment and curtail the anti-tumour immunity [6,7].

An increasing number of studies analysing the miRNA expression signatures in BC, their correlates with specific molecular subtypes and their potential clinical relevance have been reported [8-11].

The miR-200 family of miRNAs consists of five members grouped in two independent transcriptional clusters: miR-200a, 200b and 429, located on chromosome 1p36; and miR-200c and 141, located on 12p13. Deregulation of miR-200 family of microRNAs in cancer [12,13] has been related to epithelial to-mesenchymal transition and cell-plasticity, apoptotic response, molecular subtype, oestrogen regulation, control of the growth and function of stem cells and regulation of the downstream transcriptional program that mediate distant metastasis.

Also, regulatory functions of miR-200 s in tumour angiogenesis have been recently described [14]. However, in vitro and functional studies have yielded conflicting results regarding the net effect of miR-200 s in suppressing or promoting metastasis in different cellular contexts and cancer types [15-17].