Oncotarget

Research Papers:

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, Chandra Mohan KVP, Ashwani Khurana, Bruna Corominas-Faja, Elisabet Cuyàs, Tomás Alarcón, Celina Kleer, Javier A. Menendez and Ruth Lupu _

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Oncotarget. 2016; 7:71151-71168. https://doi.org/10.18632/oncotarget.9463

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Abstract

Anatilde M. Gonzalez-Guerrico1,*, Ingrid Espinoza2,3,*, Barbara Schroeder1, Cheol Hong Park1, Chandra Mohan KVP1, Ashwani Khurana1, Bruna Corominas-Faja4,5, Elisabet Cuyàs4,5, Tomás Alarcón6,7,8,9, Celina Kleer10, Javier A. Menendez4,5, Ruth Lupu1,11

1Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA

2Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

3Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA

4ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain

5Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain

6Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtica (CRM), Barcelona, Spain

7Departament de Matemàtiques, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

8ICREA (Institució Catalana d’Estudis i Recerca Avançats), Barcelona, Spain

9Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain

10Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

11Mayo Clinic Cancer Center, Rochester, MN, USA

*These authors contributed equally to this work

Correspondence to:

Ruth Lupu, email: lupu.ruth@mayo.edu

Javier A. Menendez, email: jmenendez@idibgi.org, jmenendez@iconcologia.net

Keywords: fatty acid synthase, lipogenesis, cancer, tumor reversion, phenotype

Received: February 26, 2016     Accepted: May 04, 2016     Published: May 18, 2016

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-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.


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