Fatty acid synthase confers tamoxifen resistance to er+/her2+ breast cancer

Javier A. Menendez, Adriana Papadimitropoulou, Travis Vander Steen, Elisabet Cuyàs, Bharvi P. Oza-Gajera, Sara Verdura, Ingrid Espinoza, Luciano Vellon, Inderjit Mehmi, Ruth Lupu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number1132
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2021

Keywords

  • Endocrine resistance
  • Estrogen receptor
  • Fatty acid synthase
  • HER2
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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