Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer
The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/5/1132 |
| _version_ | 1797413000110407680 |
|---|---|
| author | Javier A. Menendez Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Bharvi P. Oza-Gajera Sara Verdura Ingrid Espinoza Luciano Vellon Inderjit Mehmi Ruth Lupu |
| author_facet | Javier A. Menendez Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Bharvi P. Oza-Gajera Sara Verdura Ingrid Espinoza Luciano Vellon Inderjit Mehmi Ruth Lupu |
| author_sort | Javier A. Menendez |
| collection | DOAJ |
| description | The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on <i>FASN</i> gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of <i>FASN</i> gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas. |
| first_indexed | 2024-03-09T05:11:13Z |
| format | Article |
| id | doaj.art-96245fb7de9c4fe0b66d0e16732e627a |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T05:11:13Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-96245fb7de9c4fe0b66d0e16732e627a2023-12-03T12:49:40ZengMDPI AGCancers2072-66942021-03-01135113210.3390/cancers13051132Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast CancerJavier A. Menendez0Adriana Papadimitropoulou1Travis Vander Steen2Elisabet Cuyàs3Bharvi P. Oza-Gajera4Sara Verdura5Ingrid Espinoza6Luciano Vellon7Inderjit Mehmi8Ruth Lupu9Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007 Girona, SpainCenter of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, GreeceDepartment of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USAMetabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007 Girona, SpainDivision of Nephrology, University of Cincinnati, Cincinnati, OH 45267, USAMetabolism and Cancer Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, 17007 Girona, SpainSchool of Population Health, University of Mississippi Medical Center, Jackson, MO 39216, USAStem Cells Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires C1428ADN, ArgentinaThe Angeles Clinic & Research Institute, Cedar Sinai affiliate, Los Angeles, CA 90025, USADepartment of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN 55905, USAThe identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on <i>FASN</i> gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of <i>FASN</i> gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.https://www.mdpi.com/2072-6694/13/5/1132fatty acid synthaseendocrine resistancetamoxifenestrogen receptorHER2 |
| spellingShingle | Javier A. Menendez Adriana Papadimitropoulou Travis Vander Steen Elisabet Cuyàs Bharvi P. Oza-Gajera Sara Verdura Ingrid Espinoza Luciano Vellon Inderjit Mehmi Ruth Lupu Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer Cancers fatty acid synthase endocrine resistance tamoxifen estrogen receptor HER2 |
| title | Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer |
| title_full | Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer |
| title_fullStr | Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer |
| title_full_unstemmed | Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer |
| title_short | Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer |
| title_sort | fatty acid synthase confers tamoxifen resistance to er her2 breast cancer |
| topic | fatty acid synthase endocrine resistance tamoxifen estrogen receptor HER2 |
| url | https://www.mdpi.com/2072-6694/13/5/1132 |
| work_keys_str_mv | AT javieramenendez fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT adrianapapadimitropoulou fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT travisvandersteen fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT elisabetcuyas fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT bharvipozagajera fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT saraverdura fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT ingridespinoza fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT lucianovellon fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT inderjitmehmi fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer AT ruthlupu fattyacidsynthaseconferstamoxifenresistancetoerher2breastcancer |