Restoring Tamoxifen Sensitivity in Breast Cancer: The Role of lncRNA MALAT1 and NanoCurcumin as Modulators of Drug Resistance.

Abstract

Background: Tamoxifen resistance remains a major clinical challenge in estrogen receptor-positive (ER+) breast cancer, contributing to recurrence and poor prognosis. Long noncoding RNAs (lncRNAs), including MALAT1, UCA1, CYTOR, GAS5, and HOTAIR, have emerged as key regulators of endocrine resistance. Curcumin, a polyphenol with anticancer properties, modulates lncRNA expression, and its bioavailable formulation, NanoCurcumin, enhances therapeutic efficacy. This study evaluates the effects of NanoCurcumin in combination with tamoxifen on lncRNA expression and resistance mechanisms in ER+ breast cancer. Methods: Plasma levels of the selected lncRNAs were assessed via qRT-PCR in luminal breast cancer patients receiving tamoxifen alone or in combination with NanoCurcumin oral soft gels for 6 months. Bioinformatics analysis of MALAT1 expression was performed using the GEO database. In vitro, MALAT1 expression was evaluated in breast cancer (MCF7) and normal breast (MCF10) cell lines via qRT-PCR. Tamoxifen-resistant MCF7 cells were generated through prolonged treatment, and the effects of NanoCurcumin on MALAT1 expression were analyzed over 4 months. Results: In clinical samples, NanoCurcumin significantly reduced MALAT1 expression (p = 0.02) and trended toward decreased UCA1, CYTOR, and HOTAIR while increasing GAS5 expression. Bioinformatics analysis confirmed MALAT1 upregulation in tamoxifen-resistant cell lines. In vitro, MALAT1 was significantly elevated in MCF7 cells compared to MCF10 and increased over time with tamoxifen treatment alone. NanoCurcumin reversed this trend, sustaining low MALAT1 levels and mitigating resistance. Conclusion: Our findings suggest that NanoCurcumin mitigates tamoxifen resistance by downregulating MALAT1, offering a novel epigenetic strategy to enhance endocrine therapy efficacy. Further studies should explore lncRNA-targeted interventions to improve treatment outcomes in ER+ breast cancer.