Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases

SIMPLE SUMMARY: Early-stage invasive lobular breast cancer (ILC) is characterized by multifocal tumor growth in the breast and a distinct pattern of late metastatic spread to other tissues. ILC cells are hypothesized to initiate metastases by exiting the breast via blood and lymphatic channels early in the disease process and then invading and eventually growing in distant tissues. Using in vitro ILC models, this study reveals that expression and activation of glucocorticoid receptor (GR), a stress-hormone-activated nuclear receptor and transcription factor, resulted in inhibition of ILC cell proliferation. Unexpectedly, GR activation also appeared to increase gene expression pathways that promote metastases. Thus, GR may be an important modulator of the low proliferative rate and high late metastatic risk associated with ILC. ABSTRACT: Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC’s distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.