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<p>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 <i>FASN</i> by microRNA-449a and microRNA-449b-5p was demonstrated. Moreover, microRNAs-449 overexpression and <i>FASN</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月25日

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  • 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

摘要

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.