Loss of ERb expression as a common step in estrogen-dependent tumor progression

The characterization of estrogen receptor beta (ERb) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERb expression in cancer as compared with benign tumors or normal tissues, whereas ERa expression persists. The loss of ERb expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERa target genes by ERb or ERb-specific gene induction could explain that ERb has a differential effect on proliferation as compared with ERa. ERb may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERa and ERb expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review. Endocrine-Related Cancer (2004) 11 537–551