[PMC free article] [PubMed] [Google Scholar] 11. hormone stimuli. Through specific interaction with their cognate receptors, ovarian hormones (estrogen and progesterone) regulate the expression of a variety RO-5963 of genes that are involved in different stages of mammary gland development, including cell proliferation, differentiation, and apoptosis (13, 44, 54). It is well documented that estrogen receptor (ER) and progesterone receptor (PR) bind to palindromic response elements as homodimers and stimulate transcription of target genes by recruiting coactivators and general transcription factors (GTFs) to the promoters of hormone-responsive genes (4, 41, 63). In addition to specific hormone-receptor interactions, tissue responses to hormone stimuli are modulated by transcription cofactors. Recently, many transcription coactivators and corepressors have been identified. They regulate the magnitude of tissue responsiveness to hormone stimulation either by acting as a bridge between receptors and RO-5963 basal transcription factors and/or by changing the chromatin configuration of the promoter (14, 42, 58, 66). In regards to the effect of ovarian hormones on mammary gland tumor development, it is known that prolonged exposure to estrogenic substances significantly increases the incidence of breast cancer (22, 23, 49, 50) and hormone ablative therapy has been successfully used to inhibit ER-dependent growth of breast cancer (27). It is thus hypothesized that any genetic alteration in favor of hormone activation could result in a growth advantage and contribute to breast cancer development. It is noted that many genes overexpressed and/or amplified in breast cancer can enhance the transcription activity of steroid receptors either through ligand-independent activation, e.g., Her2 (5, 60), or by acting as steroid receptor coactivators (SRCs) such as cyclin D1 (69, 70), AIB1 (2), SRA (33, 35), PBP/PPARBP (68), and ASC-2 (34). Cdc25s (Cdc25A, -B, and -C) belong to a family of dual specificity proteins and activate cyclinCcyclin-dependent kinases (Cdks) by removal of inhibitory phosphates (11, 46). These phosphatases consist of a highly conserved catalytic domain containing an active site Cys-(X)5-Arg motif similar to the tyrosine phosphatase family and a variable N-terminal Rabbit polyclonal to AARSD1 region implicated to serve a regulatory role through phosphorylation (11, 12, 37, 38, 52, 67). Ectopic expression of Cdc25A accelerates the G1/S transition through activation of cyclin E- and cyclin A-dependent kinases that have also been shown to be able to stimulate Cdc25A, constituting a similar feedback loop in the S-phase progression (7, 24, 26). Furthermore, Cdc25 is phosphorylated in response to DNA damage to create a binding site for 14-3-3 proteins, leading to the nuclear exclusion of Cdc25 and cell cycle arrest for DNA repair RO-5963 (10, 37, 57). In accordance with their critical roles in cell cycle regulation, Cdc25A and Cdc25B have been shown to be involved in cancer progression. Cdc25A and Cdc25B, but not Cdc25C, cooperate with triggered ras to induce oncogenic focus formation of rat embryonic fibroblasts (18). Furthermore, Cdc25A and Cdc25B have been found to be overexpressed in many main tumors, including breast tumor (18, 19, 23, 31, 65). Cdc25B has been reported to have three isoform proteins, Cdc25B1, Cdc25B2 and Cdc25B3, by alternate mRNA splicing (3). Cdc25B2 appears to be most abundantly indicated in malignancy cells. Previously, transgenic mice that overexpress Cdc25B (Cdc25B2) in the mammary gland under the control of the mouse mammary tumor disease (MMTV) promoter were generated to verify the oncogenic potential of Cdc25B in vivo (39). It was found that overexpression of Cdc25B prospects to an RO-5963 increased rate of mammary epithelial cell proliferation, resulting in the formation of alveolar hyperplasia. In addition, cyclin D1 levels were elevated in these transgenic mammary glands. Cyclin D1 functions as a growth sensor, and its expression depends on extracellular signals. It has been demonstrated that cyclin D1 manifestation is directly up controlled by ER in response to hormone activation and that the enhanced manifestation mediates estrogen-induced mitogenesis (1, 51, 55, 56). An increased level of cyclin D1 mRNA was also observed in breast tumor cells overexpressing the estrogen receptor (25, 28)..