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Updated: May 20, 2025

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

Ana Lameirinhas1, Sandra Torres-Ruiz1, Iris Garrido-Cano1,2

  • 1INCLIVA Biomedical Research Institute, Valencia, 46010, Spain.

Molecular Medicine (Cambridge, Mass.)
|March 26, 2025
PubMed

Insights

MicroRNA-449 downregulation is linked to trastuzumab resistance in HER2-positive breast cancer. Targeting the microRNA-449/Fatty Acid Synthase (FASN) axis may overcome resistance and improve treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Trastuzumab is a standard therapy for HER2-positive breast cancer.
  • Therapy resistance and relapse occur in a significant patient subset.
  • MicroRNA-449 family members are downregulated in HER2-positive breast cancer, correlating with poor prognosis.

Purpose of the Study:

  • To investigate the role of microRNA-449 in trastuzumab resistance.
  • To explore the relationship between microRNA-449 and Fatty Acid Synthase (FASN) in HER2-positive breast cancer.
  • To evaluate the potential of targeting the microRNA-449/FASN axis to overcome trastuzumab resistance.

Main Methods:

  • Comparative analysis of microRNA-449 and FASN expression in trastuzumab-sensitive and resistant cell lines.
  • Demonstration of direct regulation of FASN by microRNA-449a and microRNA-449b-5p.
  • Assessment of the effects of microRNA-449 overexpression and FASN inhibition on cell proliferation and trastuzumab sensitivity.
  • Investigation of the impact on the PI3K/AKT signaling pathway.

Main Results:

  • Trastuzumab-resistant cells exhibited lower microRNA-449 and higher FASN expression.
  • MicroRNA-449 directly regulates FASN expression.
  • Overexpressing microRNA-449 or inhibiting FASN reduced cell proliferation.
  • Combined microRNA-449/FASN targeting sensitized cells to trastuzumab by inhibiting PI3K/AKT signaling.

Conclusions:

  • The microRNA-449/FASN axis is dysregulated in trastuzumab-resistant HER2-positive breast cancer.
  • Targeting this axis offers a potential strategy to overcome trastuzumab resistance.
  • Combination therapy with anti-HER2 agents and microRNA-449/FASN modulators may improve treatment response.
Keywords:
Breast cancerFASNHER2TrastuzumabmicroRNAs-449

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