Estrogen induction of the cyclin D1 promoter: Involvement of a cAMP response-like element

Abstract

Estrogens induce cell proliferation in target tissues by stimulating progression through the G 1 phase of the cell cycle. Induction of cyclin D1 expression is a critical feature of the mitogenic action of estrogen. We have determined a region between ؊96 and ؊29 in the cyclin D1 promoter that confers regulation by estrogens in the human mammary carcinoma cells MCF-7. This region encompasses a unique known transcription factor binding site with a sequence of a potential cAMP response element (CRE-D1). The induction is strictly hormone dependent and requires the DNA binding domain as well as both AF-1 and AF-2 domains of the estrogen receptor (ER) ␣. Destruction of the CRE-D1 motif caused complete loss of estrogen responsiveness. Both c-Jun and ATF-2 transactivated the cyclin D1 promoter in transient transfection experiments, and a clear additional increase was detected when ER was cotransfected with either c-Jun or with c-Jun and ATF-2 but not with ATF-2 alone. Furthermore, the expression of a dominant negative variant of c-Jun, TAM67, completely abolished the induction of the cyclin D1 promoter both in the absence and presence of ER. We show that ATF-2 homodimers and ATF-2͞c-Jun heterodimers, but not c-Jun homodimers, were able to bind the CRE of the cyclin D1 promoter. To interpret these results, we propose a mechanism in which ATF-2͞c-Jun heterodimers bind to the CRE-D1 element and mediate the activation of cyclin D1 promoter by the ER. This mechanism represents a pathway by which estrogens control the proliferation of target cells.Estrogens are decisive actors responsible for the proliferation of normal mammary epithelial cells and the development and progression of breast cancer (1). They act in early G 1 phase of the cell cycle, and both steroidal and nonsteroidal antiestrogens arrest estrogen-dependent breast cancer cells in the G 0 ͞G 1 phases (2, 3). Several studies have suggested that cyclin D1 may be involved in mediating the steroid-dependent growth of both normal and malignant mammary epithelial cells. Cyclin D1-deficient mice have a defect in steroid hormone-responsive proliferation of breast epithelium during pregnancy (4). Estrogens reinitiate the cell cycle in simvastatin-arrested MCF-7 breast cancer cells as well as the expression of cyclin D1 and phosphorylation of the retinoblastoma protein even under conditions where mitogen-activated protein kinase activity is inhibited by the continuous presence of simvastatin in the culture medium (5). Moreover, a strong correlation of increased levels of cyclin D1 mRNA with estrogen receptor (ER) overexpression in breast cancer cells has been noted (6). These results suggest a direct regulation of cyclin D1 expression by estrogens even in the absence of peptide growth factors. Thus, cell cycle control by estrogen differs from that by growth factors.Estrogens act primarily through binding to their receptor, which belongs to the steroid͞thyroid nuclear receptor superfamily (7). Like other members of the superfamily, ER␣ (NR3A1; ref. 32) exhibits a m...

Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment

“…Cyclin D1 and cdc25A behave as oestrogen-sensitive oncogenes (Altucci et al, 1996;Sabbah et al, 1999;Foster et al, 2001). Introduction of these genes in murine fibroblasts contributes to cellular transformation, and genetic alterations leading to increased expression of these genes are frequently observed in breast cancer (Quelle et al, 1993;Galaktionov et al, 1995;Michalides, 1999;Cangi et al, 2000).…”

“…Of these cyclin-cdk complexes, cyclin D-cdk4/ 6 activity drives cells through the early G1 phase of the cell cycle, whereas cyclin E-cdk2 and subsequently cyclin A-cdk2 activities are required for transition through the later G1 phase of the cell cycle past the restriction point up to which growth factor stimulation is mandatory. The mitogenic activity of oestrogen involves stimulation of expression of cyclin D1 (Altucci et al, 1996;Sabbah et al, 1999) and of cdc25A (Foster et al, 2001) an activating phosphatase of cdk2 (Jinno et al, 1994). Inhibition of oestrogen receptor activity by anti-oestrogens leads to reduced cyclin D1 expression and, as a consequence thereof, to a release of cdk-inhibitors p21 and p27 from the cyclin D-cdk4/6 complex that then become associated with cyclin-cdk2 complexes.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Cyclin proteins play a major role in G1 to S phase transition and are critical components of endocrine and paracrine factor-induced mitogenesis in breast epithelial cells [44,45]. Cyclin D1 is a target of E2 signaling [46]. Mammary epithelial cell-specific overexpression of cyclin D1 leads to mammary carcinoma; whereas in cyclin D1-deficient mice, mammary gland development is arrested before lobuloalveolar development highlighting the importance of cyclin D1 in mam-mary gland development [47].…”

“…E2-ERα regulates cyclin D1 expression by recruiting various transcription factors involve ATF-2 and c-Jun even though the cyclin D1 promoter lacks ERE or ERE-like elements [46,52]. A recent report shows that hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits ERα-mediated expression of cyclin D1 in mammary cells by curbing the recruitment of the transcription factor complex comprised of ERα, positive transcription elongation factor b (P-TEFb), and serine 2-phosphorylated RNA polymer-ase II onto CCDN1 promoter.…”

Cyclin D1: polymorphism, aberrant splicing and cancer risk

“…First, cyclin D1 mRNA levels are dramatically increased following mitogenic stimulation. This occurs in part through direct induction of the cyclin D1 promoter (Herber et al, 1994;Muller et al, 1994), such as after estrogen stimulation in breast cancer cells (Sabbah et al, 1999). Additionally, many oncogenes (e.g.…”