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

Research output: Contribution to journalArticle

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

Fingerprint

Fatty Acid Synthases
Lipogenesis
Breast Neoplasms
Phenotype
Neoplasms
Breast
Epithelial-Mesenchymal Transition
Neoplastic Stem Cells
Vimentin
Cadherins
Human Mammary Glands
Growth and Development
Fibronectins
Basement Membrane
Cues
Adipose Tissue
Cell Differentiation
Epithelial Cells
Genome
Pharmacology

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., ... 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

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. / Gonzalez-Guerrico, Anatilde M.; Espinoza, Ingrid; Schroeder, Barbara; Park, Cheol Hong; Chandra Mohan, K. V P; Khurana, Ashwani; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás; Kleer, Celina; Menendez, Javier A.; Lupu, Ruth.

In: Oncotarget, Vol. 7, No. 44, 2016, p. 71151-71168.

Research output: Contribution to journalArticle

Gonzalez-Guerrico, AM, Espinoza, I, Schroeder, B, Park, CH, Chandra Mohan, KVP, Khurana, A, Corominas-Faja, B, Cuyàs, E, Alarcón, T, Kleer, C, Menendez, JA & Lupu, R 2016, 'Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer', Oncotarget, vol. 7, no. 44, pp. 71151-71168. https://doi.org/10.18632/oncotarget.9463
Gonzalez-Guerrico AM, Espinoza I, Schroeder B, Park CH, Chandra Mohan KVP, Khurana A et al. Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. Oncotarget. 2016;7(44):71151-71168. https://doi.org/10.18632/oncotarget.9463
Gonzalez-Guerrico, Anatilde M. ; Espinoza, Ingrid ; Schroeder, Barbara ; Park, Cheol Hong ; Chandra Mohan, K. V P ; Khurana, Ashwani ; Corominas-Faja, Bruna ; Cuyàs, Elisabet ; Alarcón, Tomás ; Kleer, Celina ; Menendez, Javier A. ; Lupu, Ruth. / Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer. In: Oncotarget. 2016 ; Vol. 7, No. 44. pp. 71151-71168.
@article{b0cb1c95008c4c1b9c9ed6329defa851,
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-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.",
keywords = "Cancer, Fatty acid synthase, Lipogenesis, Phenotype, Tumor reversion",
author = "Gonzalez-Guerrico, {Anatilde M.} and Ingrid Espinoza and Barbara Schroeder and Park, {Cheol Hong} and {Chandra Mohan}, {K. V P} and Ashwani Khurana and Bruna Corominas-Faja and Elisabet Cuy{\`a}s and Tom{\'a}s Alarc{\'o}n and Celina Kleer and Menendez, {Javier A.} and Ruth Lupu",
year = "2016",
doi = "10.18632/oncotarget.9463",
language = "English (US)",
volume = "7",
pages = "71151--71168",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "44",

}

TY - JOUR

T1 - Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

AU - Gonzalez-Guerrico, Anatilde M.

AU - Espinoza, Ingrid

AU - Schroeder, Barbara

AU - Park, Cheol Hong

AU - Chandra Mohan, K. V P

AU - Khurana, Ashwani

AU - Corominas-Faja, Bruna

AU - Cuyàs, Elisabet

AU - Alarcón, Tomás

AU - Kleer, Celina

AU - Menendez, Javier A.

AU - Lupu, Ruth

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Cancer

KW - Fatty acid synthase

KW - Lipogenesis

KW - Phenotype

KW - Tumor reversion

UR - http://www.scopus.com/inward/record.url?scp=84995387578&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995387578&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.9463

DO - 10.18632/oncotarget.9463

M3 - Article

C2 - 27223424

AN - SCOPUS:84995387578

VL - 7

SP - 71151

EP - 71168

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 44

ER -