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Chronic Leptin Treatment Induces Epithelial-Mesenchymal Transition in MCF10A Mammary Epithelial Cells

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Abstract

Leptin is a cytokine-like hormone that functions as a link between obesity and breast cancer (BC). Leptin treatment induces Epithelial to Mesenchymal Transition (EMT) in BC cell lines. In non-tumoral breast epithelial MCF10A cells, acute leptin treatment induces partial EMT. However, the effect of chronic leptin treatment on EMT in non-tumorigenic breast cells has not been fully explored. This study aimed to evaluate the effect of chronic leptin treatment on the induction of EMT in MCF10A cells. We found that chronic leptin treatment induces a switch from an epithelial to a mesenchymal morphology, partial loss of E-cadherin and gain of vimentin expression. Immunolocalization experiments showed a partial loss of E-cadherin at cell junctions and increased cytoplasmic localization of vimentin in leptin-treated cells. Moreover, chronic leptin treatment increased collective cell migration and invasion. Furthermore, when cultured in non-adherent conditions leptin treated cells exhibited reduced cell aggregation, increased survival, and decreased apoptosis, which correlates with increased FAK and AKT phosphorylation. Finally, bioinformatic analysis in two publicly available RNAseq datasets from normal breast tissue shows that high levels of leptin mRNA correlate positively with the expression of mesenchymal markers, and negatively with epithelial markers. Thus, our results demonstrate that chronic leptin treatment induces EMT in non-tumorigenic MCF10A cells and suggest that high leptin expression in normal breast tissue may induce EMT and contribute to increased risk of breast cancer.

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All data generated or analyzed in this work, and detailed experimental procedures are available upon request.

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Funding

The project was founded by the “Programa de Fortalecimiento de la Calidad Educativa (PFCE)” awarded to Napoleón Navarro-Tito and Eduardo Castañeda-Saucedo (2018–2020). Juan Carlos Juárez-Cruz was awarded a PhD fellowship from the “Consejo Nacional de Ciencia y Tecnología (CONACYT)”, from 2018–2021.

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Authors and Affiliations

  1. Laboratorio de Biología Celular del Cáncer. Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero. Av. Lázaro Cárdenas S/N Ciudad Universitaria. C.P, 39087, Chilpancingo de los Bravo, Guerrero, México

    Juan Carlos Juárez-Cruz, Napoleón Navarro-Tito & Eduardo Castañeda-Saucedo

  2. Scientific IT Services ETH Zurich, ETH Zurich, Zürich, Switzerland

    Michal Okoniewski

  3. CONACYT, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, Guerrero, México

    Mónica Ramírez

  4. Laboratorio de Ácidos Nucleicos y Proteínas. Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, Guerrero, México

    Carlos Ortuño-Pineda

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  1. Juan Carlos Juárez-Cruz
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  2. Michal Okoniewski
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Contributions

JCJC, NNT and ECS contributed to the study conception and design. Material preparation, experimental procedures, and data collection were performed by JCJC. All authors contributed to data analysis and interpretation. JCJC, ECS contributed to RNAseq dataset selection and design of bioinformatic analyses, and MO performed RNAseq bioinformatic analysis and contributed to data interpretation. MR, COP contributed to data analysis and interpretation, and figure preparation. The first draft of the manuscript was written by JCJC and ECS, and all authors contributed to improving the final version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Eduardo Castañeda-Saucedo.

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Juárez-Cruz, J.C., Okoniewski, M., Ramírez, M. et al. Chronic Leptin Treatment Induces Epithelial-Mesenchymal Transition in MCF10A Mammary Epithelial Cells. J Mammary Gland Biol Neoplasia 27, 19–36 (2022). https://doi.org/10.1007/s10911-022-09515-9

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