• Non-Coding RNAs key players for overcoming drug resistance in Breast Cancer
  • Niloufar Esmaili,1 Parastesh Sadat Damadi,2 Seyed Mohsen Mirabdolhosseini,3,*
    1. Islamic Azad University, Tehran Medical Branch
    2. Islamic Azad University, Tehran Medical Branch
    3. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran


  • Introduction: Breast cancer is the most prevalent malignancy among females worldwide, with approximately 2.3 million new cases diagnosed annually. It typically originates in the ductal carcinoma or lobular carcinoma and can be categorized into non-invasive and invasive forms. Chemotherapy is the most widely used treatment for breast cancer (BC) and is known to improve patient survival rates. Common chemotherapy drugs for BC include Trastuzumab, Doxorubicin, Cisplatin agents, and Tamoxifen. However, resistance to chemotherapy remains a major challenge, as cancer cells can develop resistance, leading to tumor growth and metastasis. Factors contributing to this resistance encompass tumor heterogeneity, genetic mutations, the tumor microenvironment, metabolic reprogramming, and epigenetic alterations. It has recently reported in various resources that epigenetic emerges critical role in drug resistance. One of the recent approaches to overcome epigenetic aroused chemoresistance is through relevant molecular pariticles including long non-coding RNAs (lncRNAs), micro RNAs (miRNAs), and circular RNAs (circRNAs). Investigations in the field of the aforementioned particles have revealed their critical involvement in treatment through various molecular mechanisms, such as inhibiting apoptosis, autophagy and maintaining the stemness of breast cancer stem cells (BCSCs). In this context, we studied various therapeutic agents in which have been used commonly in breast cancer therapies and the chemoresistance phenomenon has been investigated over these drugs with a specific focus on miRNAs, lncRNAs, circRNAs to brighten this vague occurrence for future researches in order to provide an adequate resource regrading most commonly used drugs and non-coding RNAs.
  • Methods: In this review article, a comprehensive search strategy across multiple academic databases has been employed including PubMed, Google Scholar, Scopus, ResearchGate, Web of Science, and Science Direct. To achieve this goal, the search focused on a combination of keywords: "breast cancer," "epigenetic," "chemotherapy," "drug resistance," "chemoresistance", ”circRNAs”, "LncRNA," and "miRNA." This approach aimed to comprehensively explore the existing body of knowledge and emerging research trends surrounding these critical areas.
  • Results: In our study we studied the chemoresistance phenomenon in breast cancer in four most commonly used drugs including Doxorubicin, Cisplatin, Tamoxifen, and Trastuzumab. lncRNAs, miRNAs and cirRNAs as major players in this phenomenon have been studied. Regarding this occurrence we could find totally 50 specific lncRNAs, miRNAs and circRNAs that were reported as interferers for inducing drug resistance and drug sensitivity. It is worth mentioning that in our study there was a small proportion of increased drug sensitive phenomenon that was about 25% of all reports. This specific occurrence indicates that the aforementioned non-coding RNA are mostly interfere in drug resistance. While evaluating this topic it was shown that the effect of circRNAs on chemoresistant breast cancer emerges the least numbers of studies which shows that this critical field need to be evaluated more efficiently specifically concerning the Cisplatin and Trastuzumab drug resistant breast cancer. Based on our findings, there were numbers of pathways were shown to play critical roles in drug resistance. Among these pathways, BCL2, mTOR, and EMT/TGFB signalling pathways had the most repetition compared to all other signalling path ways that indicates their importance in this field. Other important finding was that some non-coding RNAs were repeated in different studies including miR-200 that used to be involved in Tamoxizen drug resistance (in two different pathways) and Doxericibin drugresistant breast cancer. In this regard, lncRNA UCA1, ZEB1 gene, and IGF1R gene, and UBE2D2 gene which shows their critical role in drug resistance and can be counted as potential topics for further evaluations.
  • Conclusion: Breast cancer (BC) remains the most prevalent malignancy and a leading cause of cancer-related mortality among women. Drug resistance poses a significant challenge, contributing to the failure of breast cancer treatments in clinical practice. This phenomenon is complex, involving numerous factors, stages, and genes. In this review, we have highlighted the discovery, development, and advancement of miRNAs, lncRNAs, and circRNAs as promising therapeutic agents for breast cancer. Despite considerable funding and research efforts, this area of translational research is still in its infancy. Moreover, our analysis revealed that certain pathways exhibited higher recurrence rates. Additionally, several interfering factors were found to be significantly more prevalent than others, suggesting that these factors may play a critical role in the progression of breast cancer and warrant further investigation in future studies.
  • Keywords: Non-coding RNAs, Drug resistance, Breast cancer, Epigenetic, Chemotherapy