Abstract
Simple SummaryOveractivation of the human epidermal growth factor receptor 2 (HER2) is one of the main drivers of tamoxifen resistance in estrogen receptor (ER)-positive breast cancer patients. Combined targeting of HER2 and ER, however, has yielded disappointing results in the clinical setting. Therefore, other potential mechanisms for tamoxifen resistance would not be overcome by solely blocking the cross-talk between ER and HER2 at the receptor(s) level. Using cell lines, animal models, and clinical data, we provide evidence to support a critical role of fatty acid synthase (FASN)—the major site for endogenous fat synthesis—in HER2-driven tamoxifen resistance. Importantly, treatment with a FASN inhibitor impeded the estrogen-like tumor-promoting effects of tamoxifen and fully restored the anti-estrogenic activity of tamoxifen in ER+/HER2-overexpressing breast cancer xenografts. We postulate FASN as a biological determinant of HER2-driven tamoxifen resistance and FASN inhibition as a novel therapeutic approach to restore tamoxifen sensitivity in endocrine-resistant 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 (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 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.
Highlights
Endocrine therapies for estrogen receptor (ER) positive (ER+) breast cancer reduce cancer recurrence and death
Indirect fluorescence microscopy revealed that fatty acid synthase (FASN) protein was localized primarily in the cytosol of untreated MCF-7 cells, a well-known model of ER+ endocrine therapy-responsive breast cancer, belonging to the luminal A molecular subtype of breast cancer (i.e., ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, and low proliferative capacity)
MCF-7 cells exposed to estradiol showed an increase in the cytoplasmic accumulation of FASN, which was notably prevented by co-exposure to tamoxifen (Figure 1A)
Summary
Endocrine therapies for estrogen receptor (ER) positive (ER+) breast cancer reduce cancer recurrence and death. Much of our knowledge of the molecular and biological mechanisms that govern endocrine resistance has come from studies showing a loss of ER expression, ER mutations, progesterone receptor negativity, and active cross-talk between ER and growth factor receptor (EGFR/HER2) pathways [1,2,3,4,5] Regarding the latter, robust clinical evidence has repeatedly suggested that human epidermal growth factor receptor 2 (HER2) overexpression confers resistance to anti-estrogen therapies, even in the presence of hormone receptors [6,7,8,9,10,11,12]. The pre-clinical observation that the activation of key transducers of metabolic signals—such as the PI3K/AKT/mTOR signaling pathway— confer endocrine resistance, has guided therapeutic strategies combining endocrine therapy with mTOR inhibitors to successfully manage endocrine-resistant breast cancer in clinical settings [16,17,18,19,20]
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