Differential expression of glucocorticoid receptor in human breast tissues and related neoplasms

Abstract

Glucocorticoid receptor (GR) is a steroid hormone receptor that has been shown to play important roles in mammary development and differentiation, and has been implicated in breast tumourigenesis, but its precise biological significance in mammary pathophysiology remains unclear. In order to generate a comprehensive expression profile for GR in normal versus neoplastic breast tissues, GR expression was investigated in situ in 400 human breast tissue samples, comprising normal tissue and a range of benign, pre-invasive, and invasive lesions, using immunohistochemical assays. The novel expression of GR in myoepithelium, not observed in luminal epithelium, not only demonstrates expression patterns exclusive to the alpha form of oestrogen receptor and progesterone receptor and suggests distinctive functions between GR and these two important steroid hormone receptors in the breast, but may also indicate unique physiological and perhaps pathological roles for the myoepithelium in mediating the effects of glucocorticoid hormones in the breast. The strong expression of GR in metaplastic carcinomas (94.4%) and malignant phyllodes tumours (92.3%) suggests a pathogenetic role for GR, and implies that targeting GR in these tumours may have potential therapeutic application. However, studies on the roles of GR in mammary carcinogenesis should be interpreted with great caution, based on the lack of GR expression in cancer cells in the great majority (98.2%) of non-metaplastic carcinomas, which has gone unnoticed in previous studies. This marked discrepancy warrants a re-examination of the biological roles of GR in the pathophysiology of breast malignancy. The lack of methylation in the promoter region of the GR gene in all 118 non-metaplastic carcinomas, as demonstrated by methylation-specific PCR and bisulphite DNA sequencing analysis, indicates that methylation is less likely to play a role in the reduction of GR expression in non-metaplastic carcinoma of the breast.