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

Int J Mol Sci. 2020 Oct 16;21(20):7661. doi: 10.3390/ijms21207661.

Abstract

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.

Keywords: endocrine resistance; fulvestrant; luminal; tamoxifen.

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Drug Resistance, Neoplasm*
  • Fatty Acid Synthase, Type I / genetics
  • Fatty Acid Synthase, Type I / metabolism*
  • Female
  • Fulvestrant / therapeutic use
  • Humans
  • MAP Kinase Signaling System
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / genetics
  • Tamoxifen / therapeutic use

Substances

  • Antineoplastic Agents, Hormonal
  • Proteins
  • histidine-rich proteins
  • Tamoxifen
  • Fulvestrant
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt