2p25.1

Breast cancers

A family of estrogen responsive genes discovered in MCF7 cells were designated GREB (genes regulated by estrogen in breast cancer) (Ghosh et al., 2000). Of these novel genes, GREB-1 was identified to have a strong correlation with ERα in breast cancer cells (Ghosh et al., 2000; Rae et al., 2005). Interestingly, GREB-1 was significantly induced by E2 in MCF-7 cells and its suppression blocked E2 induced growth (Rae et al., 2005). Furthermore, the GREB-1 regulatory region was found to possess three crucial estrogen response elements (EREs) (Lin et al., 2004). In addition, ChIP analysis revealed the binding of ERα, the steroid receptor coactivator-3, acetylated histones and phosphorylated RNA polymerase II to all three EREs in the presence of E2 (Deschênes et al., 2007). Subsequently, GREB-1 is now a well characterised estrogen responsive gene used to identify ERα activity (Cai et al., 2011; Chand et al., 2012; Gupta et al., 2012; Liu et al., 2012; Rae et al., 2005; Sun et al., 2007; Woodfield et al., 2010). Hnatyszyn, et al developed a novel GREB-1 antibody which was used to detect GREB-1 protein expression in ERα^+ve breast cancer cells and tissue (Hnatyszyn et al., 2010).
This positive correlation of GREB1 expression with ERα expression is validated in clinical cohorts (Ghosh et al., 2000). Another cohort of ER positive breast cancers in postmenopausal women (n=104) has shown a strong correlation of GREB-1 gene expression with plasma E2 levels (Dunbier et al., 2010). In a cohort of breast cancer patients (n=64) compared to healthy women (n=79) GREB-1 gene expression correlated positively with serum E2 levels (Haakensen et al., 2011). Furthermore in-vivo studies involving the transplantation of human breast tissue into female athymic mice (Balb/c nu/nu mice) has also demonstrated the induction of GREB-1 in response to E2 treatment (Wilson et al., 2006).

Prostate cancer

High levels of GREB1 mRNA ,comparable to levels in breast cancer MCF-7 cells, were found in prostatic tissues and prostate tumours (Rae et al., 2006). GREB1 was found to be also expressed in the AR-positive cell line LNCaP but absent in the AR-negative cell line PC-3 (Rae et al., 2006). GREB1 expression was responsive to androgens via androgen response elements (ARE) located ~3.3 kb upstream of the promoter. Knock-down of GREB1 in LNCaP cells led to the suppression of hormone-induced growth. Using microarray and qRT-PCR analysis of 33 prostate cancer patients, GREB1 was found to be over-expressed 13-fold compared to normal (Antunes et al., 2012). GREB1 transcript was significantly higher among patients with later stage prostate cancers.

Lung cancer

Following exposure to 2R4F tobacco mainstream smoke (MSS), GREB1 expression was elevated in normal human bronchial epithelial (NHBE) cells (Parsanejad et al., 2008). Using human saliva samples from 42 lung cancer patients and 74 healthy control subjects, transcriptomes were analyzed by gene microarray and revealed that GREB1 was one of five biomarkers found to be elevated in lung cancer patients (Zhang et al., 2012).

Ovarian cancer

To identify epigenetic changes associated with progression-free interval of ovarian cancer, 20 samples of advanced ovarian cancer with a predominantly serous papillary histological subtype were subjected to DNA methylation profiling. GREB1 promoter hypomethylation was associated with longer survival (Bauerschlag et al., 2011).

Hypertension

A SNP, 45718A>G, was significantly associated with hypertension and blood pressure level in men, and this SNP was in linkage disequilibrium with a SNP present at the 3 splice site of intron 11 (Kamide et al., 2005).