TY - JOUR
T1 - Fatty acid synthase confers tamoxifen resistance to er+/her2+ breast cancer
AU - Menendez, Javier A.
AU - Papadimitropoulou, Adriana
AU - Steen, Travis Vander
AU - Cuyàs, Elisabet
AU - Oza-Gajera, Bharvi P.
AU - Verdura, Sara
AU - Espinoza, Ingrid
AU - Vellon, Luciano
AU - Mehmi, Inderjit
AU - Lupu, Ruth
N1 - Funding Information:
Funding: This work was supported by the NIH National Cancer Institute Grant R01 CA116623 (to Ruth Lupu) and by the U.S. Department of Defense (DOD)-Breakthrough 3 Grants BC151072 and BC151072P1 (to Ruth Lupu). Work in the Menendez laboratory is supported by the Spanish Ministry of Science and Innovation (Grants SAF2016-80639-P and PID2019-10455GB-I00, Plan Nacional de l+D+I, founded by the European Regional Development Fund, Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Gi-rona). Elisabet Cuyàs holds a research contract “Miguel Servet” (CP20/00003) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (Spain).
Funding Information:
This work was supported by the NIH National Cancer Institute Grant R01 CA116623 (to Ruth Lupu) and by the U.S. Department of Defense (DOD)-Breakthrough 3 Grants BC151072 and BC151072P1 (to Ruth Lupu). Work in the Menendez laboratory is supported by the Spanish Ministry of Science and Innovation (Grants SAF2016-80639-P and PID2019-10455GB-I00, Plan Nacional de l+D+I, founded by the European Regional Development Fund, Spain) and by an unrestricted research grant from the Fundaci? Oncolliga Girona (Lliga catalana d?ajuda al malalt de c?ncer, Gi-rona). Elisabet Cuy?s holds a research contract ?Miguel Servet? (CP20/00003) from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (Spain).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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 FASN 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 FASN 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 tumorigenic-ity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely pre-vented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antago-nist 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 counter-ing resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.
AB - 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 FASN 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 FASN 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 tumorigenic-ity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely pre-vented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antago-nist 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 counter-ing resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.
KW - Endocrine resistance
KW - Estrogen receptor
KW - Fatty acid synthase
KW - HER2
KW - Tamoxifen
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UR - http://www.scopus.com/inward/citedby.url?scp=85102002639&partnerID=8YFLogxK
U2 - 10.3390/cancers13051132
DO - 10.3390/cancers13051132
M3 - Article
AN - SCOPUS:85102002639
SN - 2072-6694
VL - 13
SP - 1
EP - 19
JO - Cancers
JF - Cancers
IS - 5
M1 - 1132
ER -