Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

Anatilde M. Gonzalez-Guerrico, Ingrid Espinoza, Barbara Schroeder, Cheol Hong Park, K. V.P. Chandra Mohan, Ashwani Khurana, Bruna Corominas-Faja, Elisabet Cuyàs, Tomás Alarcón, Celina Kleer, Javier A. Menendez, Ruth Lupu

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    24 Citations (Scopus)

    Abstract

    The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-offof the angiogenic switch in FASNdepleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminallike tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normallike tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies.
    Original languageEnglish
    Pages (from-to)71151-71168
    JournalOncotarget
    Volume7
    Issue number44
    DOIs
    Publication statusPublished - 1 Jan 2016

    Keywords

    • Cancer
    • Fatty acid synthase
    • Lipogenesis
    • Phenotype
    • Tumor reversion

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  • Cite this

    Gonzalez-Guerrico, A. M., Espinoza, I., Schroeder, B., Park, C. H., Chandra Mohan, K. V. P., Khurana, A., Corominas-Faja, B., Cuyàs, E., Alarcón, T., Kleer, C., Menendez, J. A., & Lupu, R. (2016). Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget, 7(44), 71151-71168. https://doi.org/10.18632/oncotarget.9463