Breast Cancer Microenvironmental Factors that Regulate Expression of CYP19A1 in 3T3-L1 Cells

Abstract

Estrogen signaling is a critical factor that supports cancer proliferation and metastasis in breast cancer. CYP19A1 is a rate-determining enzyme that catalyzes biosynthesis of estrogen. CYP19A1 is upregulated in adipose tissue adjust to breast cancer, and enhances the local concentration of estradiol and estrogen signaling in breast cancer cells. Therefore, CYP19A1 has been considered as an important target of endocrine therapy for patients with breast cancer. In the present study, we aimed to examine expression of CYP19A1 and estrogen signaling in interaction of cancer cells and adipocytes, and to identify inflammatory, hormonal, and metabolic factors that control CYP19A1 expression in breast cancer microenvironment. First, we found that CYP19A1 expression in mature 3T3-L1 adipocytes was increased by cocultivation with MCF-7 cells. Moreover, pS2, an ERα downstream gene, was increased in cocultivated MCF-7 cells. Next, among cytokines that are abundant in cancer microenvironment, interferon-γ increased CYP19A1 protein level with 100 ng/ml for 24 h treatment in 3T3-L1 mouse preadipocytes. Also, ACTH upregulated CYP19A1 expression when cells were treated with 100 mM for 24 h. Among metabolites, saturated free fatty acids such as palmitic acids and stearic acids increased the protein level of CYP19A1, but unsaturated free fatty acids such as docosahexanoic acids and eicosapentanoic acids decreased expression of CYP19A1. Glucose also upregulated CYP19A1 expression when treated with a concentration of 20 mM for 48 h. Treatment with Interferon-γ (IFNγ), TGF-β, free fatty acids, glucose, IGF-1 was accompanied with an increase in the protein level of p204, a mouse homologue of human IFI16. These findings may help to understand CYP19A1 regulation and estrogen signaling in breast cancer microenvironment.