Involvement of microRNAs-449/FASN axis in response to trastuzumab therapy in HER2-positive breast cancer.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-03-25 DOI:10.1186/s10020-025-01163-z

Ana Lameirinhas, Sandra Torres-Ruiz, Iris Garrido-Cano, Cristina Hernando, María Teresa Martínez, Ana Rovira, Joan Albanell, Sandra Zazo, Federico Rojo, Begoña Bermejo, Ana Lluch, Juan Miguel Cejalvo, Eduardo Tormo, Pilar Eroles

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Abstract

The anti-HER2 monoclonal antibody trastuzumab and new derivative formulations are the standard treatment for HER2-positive breast cancer. However, after 1 to 5 years of treatment, some patients acquire resistance to therapy, leading to relapse. The microRNA-449 family members were downregulated in HER2-positive breast cancer cell lines and low levels were associated with patients' worse prognosis. Moreover, trastuzumab-resistant HER2-positive breast cancer cell lines showed lower microRNAs-449 and higher Fatty Acid Synthase (FASN) expression, compared to sensitive cell lines. The direct regulation of FASN by microRNA-449a and microRNA-449b-5p was demonstrated. Moreover, microRNAs-449 overexpression and FASN inhibition decreased cell proliferation and sensitized cells to trastuzumab treatment by inhibiting the PI3K/AKT signaling pathway. Together, these results suggest the microRNAs-449/FASN axis as a potential therapeutic target in combination with anti-HER2 agents to overcome trastuzumab resistance and to improve treatment response in HER2-positive breast cancer patients.

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microRNAs-449/FASN轴参与her2阳性乳腺癌曲妥珠单抗治疗反应

抗her2单克隆抗体曲妥珠单抗和新的衍生制剂是her2阳性乳腺癌的标准治疗方法。然而，经过1 ~ 5年的治疗，一些患者对治疗产生耐药性，导致复发。microRNA-449家族成员在her2阳性乳腺癌细胞系中下调，低水平与患者预后较差相关。此外，与敏感细胞系相比，曲妥珠单抗耐药her2阳性乳腺癌细胞系显示出较低的microrna -449和较高的脂肪酸合成酶（FASN）表达。证实了microRNA-449a和microRNA-449b-5p直接调控FASN。此外，microRNAs-449过表达和FASN抑制通过抑制PI3K/AKT信号通路降低细胞增殖并使细胞对曲妥珠单抗敏感。总之，这些结果表明，microRNAs-449/FASN轴作为一个潜在的治疗靶点，与抗her2药物联合，克服曲妥珠单抗耐药，改善her2阳性乳腺癌患者的治疗反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.