Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer
Gonzalez-Guerrico, Anatilde M. (Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA)
Espinoza, Ingrid (Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA)
Schroeder, Barbara (Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA)
Park, Cheol Hong (Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA)
Chandra Mohan, KVP (Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA)
Khurana, Ashwani (Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA)
Corominas-Faja, Bruna (Institut d'Investigació Biomèdica de Girona)
Cuyàs, Elisabet (Institut d'Investigació Biomèdica de Girona)
Alarcón Cor, Tomás (Universitat Autònoma de Barcelona. Departament de Matemàtiques)
Kleer, Celina (Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA)
Menendez, Javier A. (Institut d'Investigació Biomèdica de Girona)
Lupu, Ruth (Mayo Clinic Cancer Center, Rochester, MN, USA)

Fecha:	2016
Resumen:	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-off of the angiogenic switch in FASN-depleted 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 luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies.
Ayudas:	Ministerio de Economía y Competitividad SAF2012-38914 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014 SGR229
Nota:	Altres ajuts: We are greatly indebted to Prof. Robert A. Weinberg (Whitehead Institute for Biomedical Research, Cambridge, MA, USA) for providing the HMLERshCntrol and HMLERshEcad cells used in this work. Plan Nacional de I+D+I, Spain and the Departament d'Economia I Coneixement, Catalonia, Spain to Javier A. Menendez. Elisabet Cuyàs is the recipient of a "Sara Borrell" post-doctoral contract (CD15/00033, Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria -FIS-, Spain).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Fatty acid synthase ; Lipogenesis ; Cancer ; Tumor reversion ; Phenotype
Publicado en:	Oncotarget, Vol. 7 (may 2016) , p. 71151-71168, ISSN 1949-2553

DOI: 10.18632/oncotarget.9463
PMID: 27223424

18 p, 8.3 MB

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