Differential Roles for Signal Transducers and Activators of Transcription 5a and 5b in PRL Stimulation of ERα and ERβ Transcription

Abstract

PRL has been shown to stimulate mRNA expression of both ERalpha and ERbeta in the rat corpus luteum and decidua of pregnancy. To investigate whether PRL may stimulate ER expression at the level of transcription and which transcription factors may mediate this stimulation, we have cloned the 5'-flanking regions of both rat ER genes. A constitutively active PRL receptor (PRL-R(CA)) stimulated both ERalpha and ERbeta promoter activity, indicating that PRL is acting to stimulate ER transcription. Putative signal transducer and activator of transcription (Stat)5 response elements were identified at -189 in the ERalpha promoter and at -330 in the ERbeta promoter. Mutation of these response elements or overexpression of dominant negative Stat5 prevented stimulation of ERalpha and ERbeta promoter activity, indicating that PRL regulation of ER expression requires both intact Stat5 binding sites as well as functional Stat5. Interestingly, either Stat5a or Stat5b could stimulate ERalpha transcription while stimulation of ERbeta occurred only in the presence of Stat5b. Through mutational analysis, a single nucleotide difference between the ERalpha and ERbeta Stat5 response elements was shown to be responsible for the lack of Stat5a-mediated stimulation of ERbeta. These findings indicate that PRL stimulation of ER expression occurs at the level of transcription and that PRL regulation of ERalpha can be mediated by either Stat5a or Stat5b, while regulation of ERbeta appears to be mediated only by Stat5b.

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

“…PRL also increases ERa transcription after 12 hours, and Jak2 tyrosine kinase is required for this increase. 81,82 Herein, we demonstrate that PRL-mediated induction of PR gene expression occurs only after longterm treatment (ie, 48-hour treatment; Supplemental Figure S4). Although the previously described studies suggest that Stat5a is in some way required for ERa transcription, in all of these reports induction of transcription occurred only after prolonged PRL stimulation.…”

“…These reports demonstrate that constitutively active PRLr enhances transcription of ERa, as measured by an ER-luciferase reporter containing the proximal ERa promoter. 81,82 Furthermore, mutation of Stat5a binding within the proximal promoter of rat ERa prevents the PRL-mediated induction of an ER-luciferase reporter. PRL also increases ERa transcription after 12 hours, and Jak2 tyrosine kinase is required for this increase.…”

Stat5 expression predicts response to endocrine therapy and improves survival in estrogen receptor-positive breast cancer

“…Crosstalk between Stats and ER has been demonstrated by several laboratories (Stoecklin et al 1999, Yamamoto et al 2000, Faulds et al 2001, Frasor et al 2001, Bjornstrom & Sjoberg 2002a, Wang & Cheng 2004, and we have focused on the role of Stat5 in ER-positive breast cancer (Yamashita & Iwase 2002). In the present study, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed the significance for prognosis and prediction of response to endocrine therapy.…”

Naturally occurring dominant-negative Stat5 suppresses transcriptional activity of estrogen receptors and induces apoptosis in T47D breast cancer cells

“…Two studies suggest that the interactions between ERs and Stat5 involved direct physical contact via the ER DNA-binding domain (Bjornstrom et al, 2001;Faulds et al, 2001). In addition, putative Stat5 response elements were recently identified in the promoter regions of ERa and ERb, and prolactin stimulates ER expression at the level of transcription in corpus luteum (Frasor et al, 2001).…”