title: Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer.
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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anatilde M
authors.initials: AM
authors.lastname: Gonzalez-Guerrico
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Espinoza
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schroeder
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Cheol Hong
authors.initials: CH
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Chandra Mohan
authors.initials: CM
authors.lastname: Kvp
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Khurana
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: Computational and Mathematical Biology Research Group, Centre de Recerca Matemàtica (CRM), Barcelona, Spain.|Departament de Matemàtiques, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|ICREA (Institució Catalana d'Estudis i Recerca Avançats), Barcelona, Spain.|Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain.
authors.forename: Tomás
authors.initials: T
authors.lastname: Alarcón
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Celina
authors.initials: C
authors.lastname: Kleer
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.|Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA.|Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000502:physiology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D061986:MCF-7 Cells; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D064429:Fatty Acid Synthases
keywords: cancer; fatty acid synthase; lipogenesis; phenotype; tumor reversion