Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer
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 rol...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7661 |
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| author | Javier A. Menendez Inderjit Mehmi Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Luciano Vellon Ella Atlas Ruth Lupu |
| author_facet | Javier A. Menendez Inderjit Mehmi Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Luciano Vellon Ella Atlas Ruth Lupu |
| author_sort | Javier A. Menendez |
| collection | DOAJ |
| description | 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 <i>FASN</i> 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. |
| first_indexed | 2024-03-10T15:34:12Z |
| format | Article |
| id | doaj.art-1610e11586a348f199cb5dd89a3a103a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:34:12Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1610e11586a348f199cb5dd89a3a103a2023-11-20T17:22:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120766110.3390/ijms21207661Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast CancerJavier A. Menendez0Inderjit Mehmi1Adriana Papadimitropoulou2Travis Vander Steen3Elisabet Cuyàs4Sara Verdura5Ingrid Espinoza6Luciano Vellon7Ella Atlas8Ruth Lupu9Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainThe Angeles Clinic and Research Institute, Cedar Sinai affiliate, Los Angeles, CA 90025, USACenter of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, GreeceMayo Clinic, Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Rochester, MN 55905, USAProgram Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainProgram Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, SpainSchool of Population Health, University of Mississippi Medical Center, Jackson, MS 39216, USAStem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires C1428ADN, ArgentinaEnvironmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, CanadaCenter of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, GreeceHER2 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 <i>FASN</i> 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.https://www.mdpi.com/1422-0067/21/20/7661luminaltamoxifenfulvestrantendocrine resistance |
| spellingShingle | Javier A. Menendez Inderjit Mehmi Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Sara Verdura Ingrid Espinoza Luciano Vellon Ella Atlas Ruth Lupu Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer International Journal of Molecular Sciences luminal tamoxifen fulvestrant endocrine resistance |
| title | Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer |
| title_full | Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer |
| title_fullStr | Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer |
| title_full_unstemmed | Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer |
| title_short | Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer |
| title_sort | fatty acid synthase is a key enabler for endocrine resistance in heregulin overexpressing luminal b like breast cancer |
| topic | luminal tamoxifen fulvestrant endocrine resistance |
| url | https://www.mdpi.com/1422-0067/21/20/7661 |
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