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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1223-1228

Underexpression of circulating miR-145-5p and miR-133a-3p are associated with breast cancer and immunohistochemical markers


1 Laboratorio de Biomedicina y Biología Molecular, Unidad Académica de Ingeniería en Biotecnología, Universidad Politécnica de Sinaloa, Culiacán, México
2 Posgrado en Ciencias Biomédicas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, México
3 Laboratorio de Ciencias Básicas, Facultad de Odontología, Universidad Autónoma de Sinaloa, Culiacán, México
4 Departamento de Ciencias Biomédicas, Unidad Regional Mazatlán, Universidad Autónoma de Occidente

Date of Submission12-Dec-2019
Date of Decision15-Jul-2020
Date of Acceptance12-Aug-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Eliakym Arámbula-Meraz
Ciudad Universitaria, Av. Las Americas y Josefa Ortiz de Dominguez, 80010, Culiacan, Sinaloa
México
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1111_19

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 > Abstract 


Background: MicroRNAs (miRNAs) are involved in the regulation of genes with important roles in cancer. Therefore, they represent interesting targets as biomarkers for early detection, follow-up, and prognosis of the disease.
Context: In early stages of breast cancer, differences in the expression of miR-148b-3p, miR-145-5p and miR-133a-3p have been reported.
Aims: To compare the expression of miR-148b-3p, miR-145-5p and miR-133a-3p in serum samples from female patients with and without breast cancer.
Setting and Design: Case control study.
Materials and Methods: We quantified the expression by real-time polymerase chain reaction of miR-148b-3p, miR-145-5p, and miR-133a-3p in serum samples from 27 breast cancer (BC) and 17 benign breast tumor patients.
Statistical Analysis Used: Comparison between groups with categorical variables was made using the Pearson's Chi-square test. Comparative analysis for continuous variables between two groups was performed using the Student's t-test. One-way analysis of variance (ANOVA) was used for multigroup comparison, followed by Tukey HSD analysis.
Results: The use of contraceptives and a high number of births were identified as risk factors for BC. We observed that miR-145-5p expresses in low levels in BC and positively diagnosed Her2 patients. In addition, BC patients with either ductal carcinoma or positive molecular diagnosis for estrogen receptor, progesterone receptor, luminal A, or Her2 negative, presented a decreased expression of miR-133a-3p.
Conclusions: We observed an existing association between the molecular characteristics of BC and levels of circulating miR-133a-3p and miR-145-5p, proving the potential role of miRNAs as biomarkers for BC.

Keywords: Biomarkers, breast, luminal A, microRNAs, serum


How to cite this article:
Garcia-Magallanes N, Beltran-Ontiveros SA, Leal-León EA, Luque-Ortega F, Romero-Quintana JG, Osuna-Ramirez I, Barbosa-Jasso M, Arámbula-Meraz E. Underexpression of circulating miR-145-5p and miR-133a-3p are associated with breast cancer and immunohistochemical markers. J Can Res Ther 2020;16:1223-8

How to cite this URL:
Garcia-Magallanes N, Beltran-Ontiveros SA, Leal-León EA, Luque-Ortega F, Romero-Quintana JG, Osuna-Ramirez I, Barbosa-Jasso M, Arámbula-Meraz E. Underexpression of circulating miR-145-5p and miR-133a-3p are associated with breast cancer and immunohistochemical markers. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1223-8. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1223/303885




 > Introduction Top


Breast cancer (BC) is a heterogeneous disease in which genetic and environmental factors contribute to its development.[1] It is originated by an accelerated proliferation of epithelial cells.[2] In women, breast neoplasm occupies the first place in incidence and mortality worldwide, representing a quarter of all cancer cases.[3],[4] According to location, BC is mostly classified as ductal and lobular carcinoma; ductal carcinoma is the most frequent, approximately 70% of women with BC suffer from this type of cancer. On the other hand, lobular carcinoma is diagnosed in 10% of women with BC.[5],[6] In this matter, the presence of biological markers such as progesterone receptor (PR), estrogen receptor (ER), and Her2 is crucial. According to hormone receptor status, BC is classified into four subtypes, luminal A (ER and/or PR positive, Her2 negative), luminal B (ER and/or PR positive, and Her2 positive), basal-like or triple negative (ER, PR, and Her2 negative), and Her2 amplified (ER and PR negative, Her2 positive).[7] These receptors remain valid in the management of BC as a prognostic factor and to select the appropriate treatment.[8] In this field, the potential use of microRNAs (miRNAs) as biomarkers for BC has been increasing. MiRNAs are involved in the regulation of genes that play key roles in adhesion, proliferation, differentiation, motility, invasion, and cell death.[9] They may be measured in body fluids, including peripheral blood (serum and plasma).[10] In early stages of BC, differences in the expression of miR-148b-3p, miR-145-5p, and miR-133a-3p have been reported.[11],[12] The correlation of these three miRNAs with BC is mainly due to that their target genes regulate biological functions such as growth and proliferation.[11],[13],[14] Some oncogenic genes associated with miR-148b-3p are BCL2 L11, STAT3, NFKB, S1PR1, TXNIP, and EIF4E3;[15],[16],[17],[18],[19],[20] for miR-145-5p are ROCK, KLF5, HBXIP, and FSCN-1;[14],[21],[22] lastly, miR-133a-3p is related to genes that regulate cell invasion and migration such as XOS4, FSCN1, PNP, and EGFR.[23],[24],[25],[26],[27] With this in mind, the objective of the present study was to analyze the expression of miR-148b-3p, miR-145-5p, and miR-133a-3p in serum samples from female patients with and without BC, in an effort to postulate new biomarkers for BC.


 > Materials and Methods Top


Subjects

Serum samples were collected from 44 patients that attended to the Sinaloa's Institute of Cancerology. Patients were diagnosed with BC (n = 27), including patients with lobular (n = 4), ductal (n = 22), and undefined BC (n = 1), or benign breast tumor (BBT) (n = 17); the last group included women without any history of malignancies (fibroadenoma, hyperplasia, or microglandular adenosis). Our two groups included patients older than 18 years with diagnosis confirmed by histopathology, who were not receiving chemotherapy or radiotherapy, as well as not having other types of cancer. Volunteers accepted to participate in the study and signed an informed consent. Data were collected by direct questionnaire and by reviewing clinical history in the hospital database. This project was reviewed and approved by both the Ethical Committee of the Sinaloa Institute of Cancerology and the Ethical Committee of the Biomedical Science Program of the School of Chemistry and Biological Sciences at the Autonomous University of Sinaloa.

Serum samples

Blood samples were collected in tubes without anticoagulant via venous puncture. The serum was separated by centrifugation at 3000 RPM for 10 min at room temperature. All serum samples were stored at -80°C until processing.

Expression analysis of MicroRNAs

MiRNAs were obtained from 150 μL of serum using the commercial kit miRNeasy (QiagenCat No./ID: 217004) following the instructions provided by the manufacturer. Quantitative RT-qPCR was performed to obtain cDNA from corresponding miRNAs using the TaqMan® Advanced miRNA synthesis kit (Applied Biosystems). Amplification and quantification of miR-148b-3p, miR-145-5p, and miR-133a-3p were performed using qPCR TaqManTM advanced miRNA Assays probes (Applied Biosystems). In brief, 5 μL of RT preamplification product was diluted in 45 μL of RNase free water (1:10). A mixture was prepared containing 3 μL of diluted cDNA, fast advanced master mix buffer and Taqman® advanced miRNA Assay (sufficient for final concentrations of 1X for both reagents), and RNase free water to obtain a final volume of 10 μL. MiRNA expression levels were determined by quantitative real-time PCR in a StepOnePlusTM equipment (Applied Biosystems). Thermocycler conditions consisted of an initial step at 95°C for 20 s, followed by 40 cycles at 95°C for 1 s and a final step at 60°C for 20 s. Relative quantification resulted from the 2-ΔΔCq method.[28] We selected miR-16-5p as our reference gene as is a stably expressed housekeeping miRNA in BC tissue.[29]

Statistic analysis

Descriptive statistics were performed with measures of central tendency and dispersion of data based on means and standard errors for continuous variables, and based on frequency means and proportions in the case of categorical variables. A comparison between groups with categorical variables was made using the Pearson's Chi-square test. The comparative analysis for the continuous variables of two groups was performed using the Student's t-test. One-way analysis of variance (ANOVA) was used for multigroup comparisons, followed by Tukey HSD analysis. All analyses were carried out with the software package SPSS, version 22.0 (SPSS Inc. Chicago, IL, USA). A value of P < 0.05 was considered as statistically significant.


 > Results Top


Regarding the number of births, BC patients had an average of 4.30 and BBT patients an average of 2.76 (P = 0.012) as stablished by Student's t-test [Table 1]. In respect to the use of contraceptives, 36.36% of women declared to have used hormonal contraceptives, whereas 63.64% never used this type of birth control. Moreover, during Pearson's Chi-square analysis, we found an association between the use of contraceptives and BC (P = 0.017) [Table 2]. As for all other clinical variables, age, age of first pregnancy, age of last pregnancy, BMI, affected breast, breastfeeding, mammography, and family history of BC, no significant association with BC was observed [Table 1] and [Table 2]. When analyzing miR-145-5p, its expression was found 1.34 times decreased in BC patients (P = 0.027). On the contrary, in the cases of miR-148b-3p and miR-133a-3p, BC patients exhibited insignificant differences with respect to the BBT group (P values of 0.298 and 0.053, respectively); statistical analysis was conducted using Student's t-test [Figure 1]. However, when dividing patients according to BC type, results showed a significant decrease in the expression of miR-133a-3p in ductal carcinoma (P = 0.048) as stablished by one-way ANOVA (P = 0.024) and Tukey HSD; however, no differences were observed for miR-145-5p and miR-148b-3p [Figure 2]. Furthermore, when classifying tumors according to their status of molecular biomarkers ER, PR, and Her2, we observed an association between the presence of Her2 and the decreased expression of miR-145-5p in BC when compared with BBT patients (P = 0.046), and a decreased expression of miR-133a-3p in the presence of both ER and PR and the absence of Her2 in BC compared with BBT patients (P = 0.028, P = 0.031, and P = 0.041, respectively). Statistical analysis was conducted using one-way ANOVA (P = 0.021, P = 0.035, P = 0.037, and P = 0.039, respectively) and Tukey HSD [Table 3].
Figure 1: Relative expression of miR-148b-3p, miR-145-5p, and miR-133a-3p in BC and BBT patients. Bars represent mean values ± standard error, BCP = Breast cancer patients, BBTP = Benign breast tumor patients, *P < 0.05

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Figure 2: Relative expression of miR-148b-3p, miR-145-5p, and miR-133a-3p in BBTP, lobular, and ductal carcinoma. Bars represent mean values ± standard error. BBTP = Benign breast tumor patients, *P < 0.05.

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Table 1: Description and correlation between breast cancer patients and benign breast tumor patients patients

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Table 2: Correlation of clinical parameters between breast cancer and benign breast tumor patients

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Table 3: Relative expression of miR-148b-3p, miR-145-5p, and miR-133a-3p in presence of molecular biomarkers in breast cancer patients

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More importantly, we observed that BC patients that met the luminal A criteria (ER and/or PR positive, Her2 negative) showed an important decrease in the expression of miR-133a-3p (P = 0.038); statistical analysis was conducted using one-way ANOVA (P = 0.039) and Tukey HSD [Figure 3].
Figure 3: Relative expression of miR-148b-3p, miR-145-5p, and miR-133a-3p in BBTP and luminal a breast cancer. Bars represent mean values ± standard error. BBTP = Benign breast tumor patients, Luminal A (-) = Patients that do not meet the criteria for luminal A, Luminal A (+) = Patients that meet the luminal A criteria, * P < 0.05

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 > Discussion Top


In our patients, we found that a high number of births were a risk factor. Gabrielson, Chiesa[30] suggested that reproductive history influences biological mechanisms causing changes in the tissue composition via epithelial tissue compartment and hormone receptor expression. Moreover, the use of hormonal contraceptives had an association with BC. Women under the prescription of this group of drugs had a 4-fold (1.03–15.53, confidence interval (CI) 95%) increased risk of developing BC. According to the National Institute of Cancer, native hormones may influence the development of BC, thus, exogenous hormones, in the form of contraceptives, may play a role in this pathology as well.[31]

Early diagnosis is imperative to improve the prognosis of a disease; this is especially true for cancer. We observed that in our BC group, 66.7% of women were diagnosed with stage III BC or higher. These figures are in accordance with previous studies and evidence once more the necessity for a better diagnostic approach.[32]

Previous reports have claimed that family history of BC is a risk factor for the development of BC. These studies have attributed this finding to genes such as BRCA1 and BRCA2,[33],[34] however contrary to what was expected, in our study groups, we did not observe such association.

In the past, miR-148a-3p was suggested to impact the progression of gastric cancer by regulating Wnt, MAPK, and Jak-STAT signaling pathways.[35] It was also found in low levels in bladder and BC.[36],[37] However, in contrast to expectations, the expression of miR-148b-3p was unassociated to the clinicopathological characteristics considered in this study, including BC.

As previously reported by Ng et al.,[38] we observed a significant decrease in the expression of miR-145-5p in serum from BC patients, which is also demonstrated to occur in their corresponding tissue samples[12],[39],[40] In addition, the decreased expression of miR-145-5p was associated with the presence of Her2.

Lastly, low expression of miR-133a-3p was associated with specific types of BC such as luminal A and ductal, as well as with the presence of ER, PR, and the absence of Her2.[41] More importantly, luminal A possesses the highest incidence among all types of BC;[42] reports indicate that as high as 84% of patients with BC are diagnosed ER and/or PR positive and 70% Her2 negative,[41],[43],[44] thus, highlighting the importance of miR-133a-3p. There are no previous reports associating luminal A BC with miR-133a-3p. We consider this result very important since each type of BC is uniquely controlled by different genetic anomalies. In contrast to these results, miR-133a-3p showed no significant difference between BC and BBT groups, however, BC group showed an interesting decrease in relative expression. We believe that such difference may become statistically relevant with a greater sample size.


 > Conclusions Top


The main risk factors associated with BC were the number of births and the use of hormonal contraceptives. We observed a low expression of miR-145-5p in serum from BC patients. For the first time, we provided evidence about the existing association between the decreased expression of miR-145-5p and miR-133a-3p whit tumoral biomarkers in BC patients, observing this behavior in Her2 positive and luminal A tumors, respectively. Our results suggest that miR-145-5p and miR-133a-3p may play roles as tumor suppressors; miR-145-5p may assist in the diagnosis BC, and miR-133a-3p may be of use in the classification of BC. This supports the important role of miRNAs as biomarkers for cancer, thus, offering a minimally invasive diagnosis.

Acknowledgments

This work was supported by Universidad Politécnica de Sinaloa and the Instituto Sinaloense de Cancerología supplied the samples

Financial support and sponsorship

The present work was funded by the Universidad Politécnica de Sinaloa.

Conflicts of interest

There are no conflicts of interest.



 
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