ER{alpha}-regulated Lipocalin 2 Expression in Adipose Tissue Links Obesity with Breast Cancer Progression [Metabolism]

December 2nd, 2014 by Drew, B. G., Hamidi, H., Zhou, Z., Villanueva, C. J., Krum, S. A., Calkin, A. C., Parks, B. W., Ribas, V., Kalajian, N. Y., Phun, J., Daraei, P., Christofk, H. R., Hewitt, S. C., Korach, K. S., Tontonoz, P., Lusis, A. J., Slamon, D. J., Hurvitz, S. A

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of the estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knockout (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Since adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned media (CM) from ERα-null adipocytes and media containing pure Lcn2 increased proliferation and migration of a sub-set of BrCA cells in culture. The proliferative and pro-migratory effects of ERα-deficient adipocyte CM on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. Lcn2-R (slc22a17) and 3-hydroxy butyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.