Involvement of microRNAs-449/FASN axis in response to trastuzumab therapy in HER2-positive breast cancer
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.
Authors
- Federico Rojo (ORCID: https://orcid.org/0000-0001-9989-0290)
- Juan Miguel Cejalvo (ORCID: https://orcid.org/0000-0002-8755-8626)
- Begoña Bermejo (ORCID: https://orcid.org/0000-0001-7773-5994)
- Ana Lameirinhas (ORCID: https://orcid.org/0000-0003-0441-6356)
- Pîlar Eroles (ORCID: https://orcid.org/0000-0003-2708-6206)
- Aňa Lluch (ORCID: https://orcid.org/0000-0003-2766-407X)
- Joan Albanell (ORCID: https://orcid.org/0000-0003-1239-4580)
- Sandra Torres‐Ruiz (ORCID: https://orcid.org/0000-0002-7801-3560)
- Eduardo Tormo (ORCID: https://orcid.org/0000-0002-2255-785X)
- Cristina Hernándo (ORCID: https://orcid.org/0000-0002-6865-4196)
- Ana Rovira (ORCID: https://orcid.org/0000-0003-1301-2599)
- Iris Garrido‐Cano (ORCID: https://orcid.org/0000-0002-1211-473X)
- Sandra Zazo
- María Teresa Martínez (ORCID: https://orcid.org/0000-0003-1312-3555)
Institutions
- Universitat de València (ES)
- Hospital Clínico Universitario de Valencia (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Hospital Del Mar (ES)
- Municipal Institute for Medical Research (ES)
- Hospital del Mar Research Institute (ES)
- INCLIVA Health Research Institute (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat Politècnica de València (ES)
Publication Details
- Journal
- Molecular Medicine
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1186/s10020-025-01163-z
- Citations
- 2
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- American Concrete Institute Foundation
- European Commission
- Generalitat Valenciana
- Sociedad Española de Oncología Médica
- Centro de Investigación Biomédica en Red de Cáncer