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.
Highlights
Patients with estrogen receptor (ER)-positive (ER+) breast cancer can benefit from long-term endocrine treatment
We first evaluated whether HRG overexpression and autocrine transactivation of HER2, independently of HER2 overexpression, might lead to the up-regulation of tumor-associated fatty acid synthase (FASN) in an in vitro model of endocrine resistant, luminal B-like breast cancer (Figure 1A, top panel)
We evaluated FASN protein expression in an HRG-overexpressing model of biologically aggressive, endocrine-resistant ER+ breast cancer developed in our laboratory by transducing MCF-7 breast cancer cells with a retroviral vector containing the HRG cDNA (MCF-7/HRG cells [18])
Summary
Patients with estrogen receptor (ER)-positive (ER+) breast cancer can benefit from long-term endocrine treatment. Specific tumor phenotypic traits are important in determining the prognosis of women with ER+ breast cancer undergoing treatment with selective ER modulators (SERMs) and down-regulators (SERDs) such as tamoxifen and fulvestrant (formerly ICI 182,780), respectively [1,2,3,4,5]. Luminal A MCF-7 breast cancer cells, which are normally highly sensitive to tamoxifen in vitro, can overcome the anti-proliferative effects of tamoxifen when exogenously treated with the HER3 ligand heregulin (HRG) by enriching for the growth factor signaling gene set and activating a proliferative signature similar to that of tamoxifen-resistant ER+ luminal B-type tumors [11]. Beyond the expected hyperactivation of downstream signaling pathways such as ERK/MAPK and PI-3K/AKT, there remains a paucity of research into identifying prominent molecular targets that could be of therapeutic benefit in tamoxifen-refractory HRG+/HER2− luminal B-like breast carcinoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
