Role for Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) in Hormone-Dependent Cancers

Abstract

Sex hormones play important roles in the onset and progression of several cancers, such as breast, ovarian, and prostate cancer. Although drugs targeting sex hormone function are useful in treating cancer, tumors often develop resistance. Thus, we need to define the downstream effectors of sex hormones in order to develop new treatment strategies for these cancers. Recent studies unearthed one potential mediator of steroid hormone action in tumors: growth regulation by estrogen in breast cancer 1 (GREB1). GREB1 is an early estrogen-responsive gene, and its expression is correlated with estrogen levels in breast cancer patients. Additionally, GREB1 responds to androgen in prostate cancer cells, and can stimulate the proliferation of breast, ovarian, and prostate cancer cells. Recent studies have shown that GREB1 also responds to progesterone in human endometrial cells, suggesting that GREB1 is a pan steroid-responsive gene. This mini-review examines evidence that GREB1 participates in several hormone-dependent cancers and could be targeted to treat these cancers.

Keywords: GREB1; androgen; breast cancer; estrogen; ovarian cancer; progesterone; prostate cancer; steroid hormone.

Figure 1

Model of the classic hormone-signaling pathway. The hormone enters the cell andbinds to a hormone receptor (HR). The arrows represent steps involved in activation of HR by its hormone. The HR forms a homodimer, undergoes a structural change to expose the hormone response element (HRE) binding domain, and enters the nucleus. Then, in conjunction with coactivators, HR binds an HRE to modulate the transcription of downstream genes such as GREB1. The arrows represent steps involved in activation of HR by its hormone.

Figure 2

Model of growth regulation by estrogen in breast cancer 1 (GREB1) structure and transcription. The human GREB1 gene is located on 2p25.1. Three upstream estrogen response elements (EREs) located at −21.2, −9.5, and −1.6 kb and one androgen response element (ARE) located at −3.3 kb can modulate GREB1 transcription. The GREB1 gene produces at least three isoforms: GREB1a (NM_014668.3 → NP_055483.2), GREB1b (NM_033090.2 → NP_149081.1), and GREB1c (NM_148903.2 → NP_683701.2), which have alternate 5′ and 3′ UTRs. Splicing after exons 10 and 9 results in short GREB1b and GREB1c isoforms, respectively. The GREB1a protein contains two LXXLL motifs and a superfamily II (SFII) helicase module fused with a glycosyltransferase (TAGT) motif in the C-terminus.