PRL Activates the Cyclin D1 Promoter Via the Jak2/Stat Pathway

Abstract

PRL promotes cell growth and differentiation in the mammary gland, which has implications for breast cancer as well as normal development. Our data demonstrate that PRL significantly increases proliferation of mammary carcinoma cells. PRL also increases cyclin D1 levels 2-fold, which can be inhibited by actinomycin D, suggesting that transcriptional increases in cyclin D1 are important. Using a defined Chinese hamster ovary cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increases after PRL treatment. Furthermore, this increase in promoter activity is predominantly mediated by the Jak2/Stat5 signaling pathway. The cyclin D1 promoter contains two consensus sequences for PRL-induced Stat binding (GAS sites). Disruption of Stat binding to the distal GAS site destroys PRL-induced promoter activity, whereas disruption of the proximal site has no effect. We have shown by EMSA that PRL induces Stat5a and 5b to bind to the distal GAS site, and immunoprecipitation and subsequent Western analysis of nuclear extracts from PRL-treated cells indicate that Stat5a and 5b can interact as a heterodimer in this system. These data suggest that cyclin D1 may be a target gene for PRL in normal lobuloalveolar development, as well as in the development and/or progression of mammary cancer.

The Prolactin Receptor Transactivation Domain Is Associated with Steroid Hormone Receptor Expression and Malignant Progression of Breast Cancer

“…Normal, normal breast tissue; Tumor, primary breast tumor; LN Met, lymph node metastasis. *P < 0.05, **P < 0.01, and ***P < 0.001. such as CCND1 63,64 and C/EBPb, 65 we also identified several novel PRL-induced genes, such as dexamethasoneinduced Ras-related protein 1 (RASD1), MYADM, and ZYX. These novel PRL-induced target genes are significant for the following reasons: i) RASD1 functions as a tumor suppressor gene by inhibiting cell growth, 66 ii) MYADM is important for the organization of lamellipodium extension and cell motility, 67 and iii) reports suggest that ZYX is a critical regulator of DNA damageeinduced cell death induction.…”

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

“…This can also be seen in transgenic mice, where targeted overexpression of cyclin D1 in mammary epithelial cells leads to tumor formation (Wang et al, 1994). These observations suggest that strict control of cyclin D1 expression in mammary epithelial cells is necessary to separate normal development from oncogenesis (Brockman et al, 2002). Thus, two central processes in tumor biology appear to be hypoxia and cyclin D1 overexpression.…”

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

“…CHO cells were used for cDNA overexpression studies as they express low or undetectable levels of Nek3, Vav2 and the PRLr (Miller et al, 2005). Transfection of the PRLr alone into CHO cells, followed by PRL stimulation, resulted in the activation of the Jak2/STAT5 (Brockman et al, 2002), MAPK (Gao and Horseman, 1999) and Vav/Rac1 (Miller et al, 2005) signaling pathways, demonstrating the responsiveness of CHO transfectants to PRL. Therefore, we hypothesized that overexpression of Nek3 and Vav2 in this system might lead to significant changes in the actin cytoskeleton in response to PRL.…”