Abstract
Metformin, a drug approved for diabetes type II treatment, has been associated with a reduction in the incidence of breast cancer and metastasis and increased survival in diabetic breast cancer patients. High levels of miR-26a expression have been proposed as one of the possible mechanisms for this effect; likewise, this miRNA has also been associated with survival/apoptosis processes in breast cancer. Our aim was to evaluate if miR-26a and some of its targets could mediate the effect of metformin in breast cancer. The viability of MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cell lines was evaluated with an MTT assay after ectopic overexpression and/or downregulation of miR-26a. Similarly, the expression levels of the miR-26a targets CASP3, CCNE2, ABL2, APAF1, XIAP, BCL-2, PTEN, p53, E2F3, CDC25A, BCL2L1, MCL-1, EZH2, and MTDH were assessed by quantitative polymerase chain reaction (PCR). The effect of metformin treatment on breast cancer cell viability and miR-26a, BCL-2, PTEN, MCL-1, EZH2, and MTDH modulation were evaluated. Wound healing experiments were performed to analyze the effect of miR-26a and metformin treatment on cell migration. MiR-26a overexpression resulted in a reduction in cell viability that was partially recovered by inhibiting it. E2F3, MCL-1, EZH2, MTDH, and PTEN were downregulated by miR-26a and the PTEN (phosphatase and tensin homolog) protein was also reduced after miR-26a overexpression. Metformin treatment reduced breast cancer cell viability, increased miR-26a expression, and led to a reduction in BCL-2, EZH2, and PTEN expression. miR-26a inhibition partly prevents the metformin viability effect and the PTEN and EZH2 expression reduction. Our results indicate that metformin effectively reduces breast cancer cell viability and suggests that the effects of the drug are mediated by an increase in miR-26a expression and a reduction of its targets, PTEN and EHZ2 Thus, the use of metformin in breast cancer treatment constitutes a promising potential breast cancer therapy.
Highlights
Breast cancer is the most frequent cancer among women worldwide and the leading cause of death by cancer in women [1]
We evaluated the expression of these 11 genes in the three breast cancer cell lines, after transfecting them with a miR-26a mimetic or inhibitor, by RT-qPCR
PTEN and E2F3 downregulation after miR-26a transfection was the most relevant finding because it suggests that this miRNA directly targets genes; this was especially interesting for PTEN as it has proven relevance in cancer processes
Summary
Breast cancer is the most frequent cancer among women worldwide and the leading cause of death by cancer in women [1]. In the year 2000, Perou et al [4] classified it into five molecular subtypes according to its intrinsic genetic signature, immunohistochemical classification is still used in clinics. Treatment is based on the differential characteristics of breast cancer subtypes and is largely successful in human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) positive (luminal) cancers (using anti-HER2+ and hormonal therapies, respectively). In triple negative breast cancer (TNBC; HER2, ER, and progesterone receptor negative), representing about 15%–20% of all breast cancer patients, there are no well-defined molecular targets. This subtype is related to anIentl.eJv. Matoel.dScri.e2c0u16r,r1e7n, 1c2e98rate, worse prognosis and a lower survival rate compared to other ty pofe1s5 of Tbrheirtasyeslppateetcsecaduonlftcioaberrraietn[ay5s,e,t6ale]cnvaddanutcteehed,rear[fm5ea,cc6out]nrtdrgheuanoetct,hteaaemrrragotreeent,aegwdsooottnrrhessee,arttpomrretoeahgnseontsnhosisen,itsetHoraonEtghdRee2anh+eleoiattwenyrdeoargnEsedRunr+aevgibtigvyreraaealnssrsdtaitcvaeaegncgnocrmaeetrsupssariaverreeeodnfntaToottNuoarBtelhwCoearf[y6s]. IInn 22001144,,YYaannggeettaal.l.[2[12]1]ddememonosntrsatrteadtedthatht at memtfoetrfmorimn iinnhinibhiibtsitrserneanlaclacnancecrercceellllggrroowwtthhbbyy iinndduucciinnggoovveerreexxpprreessssioionnoof fthteheonocnocgoegneinc imc imcriocRroNRAN, A, miRm-i2R6-a2,6wa,hwichhichhashBaCs LB-C2La-n2daPnTdEPNTaEmNoanmgoitnsgtairtgs ettasr.gIentst.hiIsnstthuidsystwuedyaimweedatiomdedetetormdienteerimf minieR-i2f6a andm/iRor-2s6oamaendo/foirtsseofmfeectoofrittsaregfefetsctaorretaimrgpeltiscaatreediminptlhiceataendtiitnumthoe raenftfietuctmoofrmefeftefcotrmofinmientfoTrNmBinC iannd ERT+NbBreCasatncdanEcRe+rb, rpeaarstticcuanlacrelry, pinarcteiclluvlaiarlbyiliintycealnl dvi/aobrilmityigarnadti/oonr .migration
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