Osteopontin promotes aromatase expression and estradiol production in human adipocytes

Breast and endometrial cancer are often estrogen dependent, and their incidence and mortality are increased by obesity in postmenopausal women. Osteopontin (OPN) is a cytokine strongly upregulated in adipose tissue (AT) in obesity. OPN function is potentiated by cleavage by matrix metalloproteinases (MMP). OPN and MMPs play a role in cancer development and are prognostic markers in breast cancer progression. While induction of the estrogen-synthesizing enzyme aromatase by TNFa and IL1 has been shown in preadipocytes, an impact of OPN on aromatase expression in AT has not been investigated yet. Gene expression was determined in AT samples of 21 morbidly obese and matched non-obese subjects. Primary human adipocytes were treated with full-length OPN or MMP-cleaved OPN (cOPN). Protein and mRNA expressions were analyzed from cell lysates, or cells were subsequently supplied with testosterone to determine estradiol production and for indirect co-culture with the estrogen-dependent MCF-7 cell line. Aromatase expression strongly correlated with gene expression of OPN and various MMPs in visceral and MMPs in subcutaneous AT, but not with TNFα expression in both tissues. In vitro, cOPN more effectively than full-length OPN upregulated aromatase mRNA in adipocytes and significantly increased aromatase protein level and estradiol production, leading to increased MCF-7 growth in indirect co-culture. OPN and MMPs are upregulated in AT in obesity, and MMP-cleaved OPN is particularly effective in inducing aromatase activity in human adipocytes. Thereby, obesity-induced OPN expression in AT may contribute to estradiol production and thus to the association of obesity with estrogen-dependent cancers.