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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21 Scopus citations

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 (US)
Pages (from-to)71151-71168
Number of pages18
JournalOncotarget
Volume7
Issue number44
DOIs
StatePublished - 2016

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Keywords

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

ASJC Scopus subject areas

  • Oncology

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