TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

Abstract

The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. The steroid hormones estrogen and progesterone play key roles in the growth of the mammary gland (49). Estrogens appear to be the main drive for proliferation of the mammary gland epithelium, whereas progesterone is required for its terminal growth and differentiation (27). The induction of mammary epithelial development during pregnancy is mediated by a rise in progesterone levels (51). The physiological effects of progesterone occur mainly via interaction with specific intracellular progesterone receptors (PRs), PR-A and PR-B, which are products of a single gene and members of the nuclear receptor (NR) family (11). Studies performed on mice in which the expression of both PRs was ablated have demonstrated that progesterone is necessary for ductal branching and the lobulo-alveolar development of the mammary gland (45). More recently, selective ablation of each receptor isoform has indicated that PR-B is specifically required for the progesterone-dependent development of the mammary gland during pregnancy (11).In relation to the function of progesterone in breast development, both growth-stimulatory and -inhibitory effects have been previously reported on breast epithelium cells and cancer development in tumor animal models (11,42,46). Moreover, in vitro studies using the PR-positive mammary carcinoma T47D cell line as a model have demonstrated a biphasic cellular response to either progesterone or its derivatives (R5020 or ORG 2058), with an immediate proliferative burst followed by a sustained growth arrest (28,38,50). As with many hormones and growth factors, the regulation of retinoblastoma gene product (pRB) phosphorylation-a critical checkpoint of the G 1 /S transition-plays a major role in the control of proliferation by progesterone (18,39,71). The initial pRB phosphorylation provoked by progesterone is catalyzed by constitutively expressed cyclin-dependent kinases (CDKs), which are activated through interaction with specific cyclins induced by progesterone (39). The ensuing growth arrest is associated, at least in part, with the transitory induction of the cyclin-dependent kinase inhibitors (CDKIs) p21Cip1/WAF1 (p21) and p18 INK4c(p18), followed by a sustained induction of p27 Kip1 (p27) (28,

The molecular basis of progesterone receptor action in breast carcinogenesis

“…In the case of p21 CIP1 , progestins modulate its expression via PR tethering to the TF SP1 at the third and fourth SP1 binding sites in the p21 CIP1 promoter [86 -88] . Similar interaction between PR and SP1 at the p27 KIP1 promoter has also been found [87] . The coactivators CBP/p300 and TReP-132 are corecruited along with SP-1 and PR to p21 CIP1 and p27 KIP1 promoters [87] .…”

“…Similar interaction between PR and SP1 at the p27 KIP1 promoter has also been found [87] . The coactivators CBP/p300 and TReP-132 are corecruited along with SP-1 and PR to p21 CIP1 and p27 KIP1 promoters [87] . This tethering mechanism raises an exciting question: does PR rapid stimulation of signaling pathways induce the phosphorylation of TFs that in turn participate in non-classical PR transcriptional tethering mechanisms ?…”

Progesterone Receptor Inhibits Proliferation of Human Breast Cancer Cells via Induction of MAPK Phosphatase 1 (MKP-1/DUSP1)

“…We observed that the anti-inflammatory actions of PR are mediated by ligand-dependent and -independent mechanisms, resulting in an inhibition of NF-B activation with consequent down-regulation of hCOX-2, aromatase/hCYP19, and HER-2/neu expression (44). Notably, MKP-1 mRNA expression was observed to be induced by P 4 /PR in human breast cancer cells (22).…”

Functional identification of genes causing estrogen independence of human breast cancer cells

“…Within the nuclear compartment, NCOR2 participates in a co-repressor complex resulting in chromatin condensation and may also modulate ligand dependency of hormone receptors and contribute to estrogen independency [34][35][36]. TRERF1 was reported to negatively modulate breast cancer cell proliferation by upregulation of G1 cyclin-dependent kinase inhibitors and through co-activation of the progesterone receptor [23,37]. Whether the transcription regulators CITED2 and TLE3 fit into the same pathways as the cytoplasmic targets or represent alternative signaling routes, remains an intriguing question.…”