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Open AccessArticle

Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

1
Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, Spain
2
Girona Biomedical Research Institute (IDIBGI), 17190 Girona, Spain
3
The Angeles Clinic and Research Institute, Cedar Sinai affiliate, Los Angeles, CA 90025, USA
4
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
5
Mayo Clinic, Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USA
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School of Population Health, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Cancer Institute, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Stem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires C1428ADN, Argentina
9
Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada
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Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
11
Mayo Clinic Minnesota, Department of Biochemistry and Molecular Biology Laboratory, Rochester, MN 55905, USA
12
Mayo Clinic Cancer Center, Rochester, MN 55905, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7661; https://doi.org/10.3390/ijms21207661
Received: 28 September 2020 / Revised: 12 October 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer. View Full-Text
Keywords: luminal; tamoxifen; fulvestrant; endocrine resistance luminal; tamoxifen; fulvestrant; endocrine resistance
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MDPI and ACS Style

Menendez, J.A.; Mehmi, I.; Papadimitropoulou, A.; Vander Steen, T.; Cuyàs, E.; Verdura, S.; Espinoza, I.; Vellon, L.; Atlas, E.; Lupu, R. Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer. Int. J. Mol. Sci. 2020, 21, 7661.

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