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Spanish

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http://hdl.handle.net/10251/124005

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Study of possible myR-99a microRNA targets in triple negative breast cancer

Abstract

[EN] Currently, cancer is the second most prevalent disease worldwide, with a number of affected patients that has been doubled in the last decade. Specifically, breast cancer is the type of tumour more frequently diagnosed in women, being the triple negative subtype characterised by its agressivity and poor prospects due to the absence of candidate targets for treatment, since this type of tumour lacks the PGR, ER and HER2 receptors. Thereby, therapeutic alternatives for these patients are restricted to unspecific conventional chemotherapies, such as doxorubicin and some taxanes. The development of chemotherapy resistances is one of the poor prognosis factors in triple negative breast cancer. Several studies have been conducted in order to reveal the molecular mechanisms underlying the development of chemoresistance. MicroRNAs have been described to play an essential role not only in the progression of the disease, but also in the development of chemoresistances, since microRNAs can target oncogenes or tumour supressor genes. In fact, many microRNAs have been already classified as oncomiRs or tumour supressor microRNAs. This work is the continuation of a previous study, in which a microRNAs microarray was performed to compare the expression profiles of microRNAs between sensitive and resistant to doxorubicin triple negative breast cancer MDA-MB-231 cell lines. This analysis revealed that microRNA miR-99a-5p is differentially expressed, exhibiting significantly lower levels of expression in the resistant cell line, suggesting a tumour suppressing role. Based on the suggested implication of microRNA miR-99a-5p in resistance to doxorubicin, the present investigation aimed to reveal the molecular mechanisms that imply miR-99a-5p in the development of chemoresistance. For that purpose, a search of possible miR-99a-5p targets was conducted by the use of bioinformatic target prediction tools, being COX2 and ABCG2 identified as feasible targets. In order to determine whether miR-99a-5p regulates the expression of COX2 and ABCG2, the microRNA was overexpressed and inhibited and afterwards the expression levels of the hypothetical targets were determined by real time PCR and by Western Blotting in order to assess the changes at gene and protein levels. Eventually, the reporter gene assay was performed in order to determine whether miR-99a regulates COX2 and ABCG2 expression in a direct or indirect manner. TFGM

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