Abstract
Our early studies have shown that Estradiol (E2)/Estrogen Receptor α (ER) in a non-DNA dependent manner through complex formation with C/EBPβ/SP1 induced transcriptional activation of the generic hPIII promoter and expression of the Prolactin Receptor (PRLR) receptor in MCF-7 cells. Subsequent studies demonstrated effects of unliganded ERα with requisite participation of endogenous PRL on the activation of PRLR transcription. Also, EGF/ERBB1 in the absence of PRL and E2 effectively induced upregulation of the PRLR. In this study we have delineated the transcriptional mechanism of upregulation of PRLR receptor induced by E2 incorporating knowledge of the various transcriptional upregulation modalities from our previous studies. Here, we demonstrate an essential requirement of STAT5a induced by PRL via PRLR receptor which associates at the promoter and its interaction with phoshoERα S118. Knock-down of PRL by siRNA significantly reduced E2-induced PRLR promoter activity, mRNA and protein expression, recruitment of ERα to the complex at promoter, C/EBPβ association to its DNA site and productive complex formation at hPIII promoter. The specific CDK7 inhibitor (THZ1) that attenuates E2-induced ERα phosphorylation at S118 abrogated E2-induced PRLR promoter activation. Further studies demonstrated that E2 induced cell migration was inhibited by PRL siRNA and THZ1 indicating its dependence on PRL/PRLR and CDK7, respectively. Our studies have demonstrated the essential role of endogenous PRL and CDK7 in the upregulation of PRLR by E2 and provide insights for therapeutic approaches that will mitigate the transcription/expression of PRLR and its participation in breast cancer progression fueled by E2 and PRL via their cognate receptors.
Highlights
Prolactin Receptor (PRLR) belongs to the class I cytokine receptor superfamily
In previous studies we determined that endogenous PRL which is present in breast cancer cells contributes to basal levels of PRLR expression in MCF-7 and T47D cells and these were magnified by addition of exogenous PRL
These findings indicate that endogenous PRL is required for the increases in PRLR induced by E2 in breast cancer cells
Summary
Prolactin Receptor (PRLR) belongs to the class I cytokine receptor superfamily. The long form of PRLR has an extracellular domain, a single transmembrane domain and intracellular cytoplasmic domain which is required for signal transduction. Prolactin (PRL) hormone binds to PRLR with high affinity and mediates its actions predominantly through JAK-2/STAT5 signaling pathway and other pathways that involve MAPK and the participation of JAK2/c-SRC family kinases/ focal adhesion kinase via phosphatidylinositol 3-kinase [1,2,3]. PRLR is well known to play an important role in the physiology of the human breast and in the etiology, progression breast cancer [4,5,6]. Substantial clinical and etiological evidence indicates that estrogen exposure promotes the development, progression and invasion of breast cancer. Its effects are mediated via estrogen receptors through a host of estrogen responsive genes [7,8,9], and through signaling pathways generate through nongenomic pathways [10]. An important connection has been established between ERα and PRLR where both liganded www.impactjournals.com/oncotarget and un-liganded ERα were found to participate in PRLR regulation [12, 13]
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