Integration of progesterone receptor action with rapid signaling events in breast cancer models

Lange, Carol A.

doi:10.1016/j.jsbmb.2007.09.019

Cited by 58 publications

(62 citation statements)

References 86 publications

(144 reference statements)

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“…In several reports, this type of post-translational modification has been shown to alter receptor transcriptional activation, stability, localization, and protein complex formation (Lange 2008, Daniel et al 2009, Knutson et al 2012. Previous findings in hFSH-treated rats showed that calyculin (a potent inhibitor of intracellular phosphatases; Condrescu et al 1999) reduced the inhibitory action of hFSH on LH secretion in a dose-dependent manner (Gordon et al 2009b).…”

Section: Discussionmentioning

confidence: 97%

“…PR is a phosphoprotein that contains several phosphorylation sites, Ser residues, which are susceptible to constitutive or ligand-induced modification (Lange 2008). In several reports, this type of post-translational modification has been shown to alter receptor transcriptional activation, stability, localization, and protein complex formation (Lange 2008, Daniel et al 2009, Knutson et al 2012.…”

Section: Discussionmentioning

confidence: 99%

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Understanding the regulation of pituitary progesterone receptor expression and phosphorylation

et al. 2015

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Administration of human FSH (hFSH) during the diestrus phase in cyclic rats is followed by a reduction in the preovulatory LH surge. This inhibitory action of FSH involves a decrease in the stimulatory effect of gonadotrope progesterone receptor (PR) activation, in a ligand-dependent (progesterone) and -independent (GNRH) manner. PR activation and action are mandatory for LH surge, and are dependent on the phosphorylation of serine (Ser) residues. Together with this post-translational modification, PR is marked for downregulation by proteasome machinery. These experiments used the western blotting technique to measure pituitary expression of PR-A and PR-B isoforms and phosphorylation levels of Ser294 and Ser400 PR-B in rats bearing i) hFSH treatment or ii) PR downregulation. Treatment with hFSH reduced LH secretion and increased that of estradiol in proestrus afternoon. hFSH injections, without altering PR-A and PR-B content or ratio, caused a reduction in phosphorylation of Ser294 and Ser400 but only when pituitaries were previously challenged with progesterone or GNRH for 2 h. However, while pSer294 levels increased after 2 h of pituitary incubation with progesterone or GNRH, those of pSer400 were not modified by these in vitro treatments. Finally, progesterone had a biphasic effect: in 2-h incubations increased pituitary PR-A and PR-B content, but after 8 h caused downregulation and altered PR-A:PR-B ratio. The results provide a potential mechanism through which LH levels are decreased by hFSH administration and better understanding of the control of PR expression and phosphorylation in rat pituitaries.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Understanding the regulation of pituitary progesterone receptor expression and phosphorylation

et al. 2015

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“…This convergence of ER␣ and ERK2 at the chromatin level is critical in ERK2 support of estrogen and ER␣ activities that regulate gene expression programs and cell cycle progression. That the MAPK pathway has been shown to also regulate gene expression by androgen receptor in prostate cancer cells (1) and by progesterone receptor in breast cancer cells (10,11,25,41) suggests that the paradigm of convergence and functional collaboration of these two proteins that we have defined at the genome level may be more universal and likely will be observed for other members of the large nuclear receptor superfamily of proteins.…”

Section: Discussionmentioning

confidence: 98%

Genomic Collaboration of Estrogen Receptor α and Extracellular Signal-Regulated Kinase 2 in Regulating Gene and Proliferation Programs

Madak-Erdoğan

Lupien

Stossi

et al. 2011

Molecular and Cellular Biology

104

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The nuclear hormone receptor, estrogen receptor ␣ (ER␣), and mitogen-activated protein kinases (MAPKs) play key roles in hormone-dependent cancers, and yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ER␣ activates and interacts with extracellular signal-regulated kinase 2 (ERK2), a downstream effector in the MAPK pathway, resulting in ERK2 and ER␣ colocalization at chromatin binding sites across the genome of breast cancer cells. This genomic colocalization, predominantly at conserved distal enhancer sites, requires the activation of both ER␣ and ERK2 and enables ERK2 modulation of estrogen-dependent gene expression and proliferation programs. The ERK2 substrate CREB1 was also activated and recruited to ERK2-bound chromatin following estrogen treatment and found to cooperate with ER␣/ERK2 in regulating gene transcription and cell cycle progression. Our study reveals a novel paradigm with convergence of ERK2 and ER␣ at the chromatin level that positions this kinase to support nuclear receptor activities in crucial and direct ways, a mode of collaboration likely to underlie MAPK regulation of gene expression by other nuclear receptors as well.Estrogen receptor ␣ (ER␣), a member of the large superfamily of nuclear receptors, exerts profound effects on the gene expression, cellular response programs, and phenotypic properties of estrogen target cells, including over 70% of breast cancers. This hormone receptor also plays a central role in breast cancer development and progression. Because of these broad and important actions, ER␣ is usually considered the single most crucial predictor of breast cancer prognosis and is the key target of endocrine therapies. Blocking the activity of this receptor protein by use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors, which reduce estrogen production, has proven highly effective in targeted treatment of hormone-responsive breast cancers (23,24,37) and also in the prevention of breast cancer in women at high risk for the disease (42).Increased activity of the mitogen-activated protein kinase (MAPK) pathway is one of the hallmarks of more aggressive cancers and of endocrine resistance, in which ER␣-positive tumors become refractory to endocrine therapies and relapse. It is believed that the balance of control of cellular physiology switches from ER␣ nuclear-initiated pathways to increased involvement of extranuclear-activated protein kinase pathways in these breast cancers (5,20,23,32,38,39). However, the interplay and integration of the signaling inputs of this nuclear hormone receptor and MAPKs are poorly understood and were therefore aspects we examined here.The MAPK family comprises well-conserved proteins that function as downstream effectors of a multitier signaling cascade, including a MAPK kinase (MAPKK, MEK) and a MAPKK kinase (MAPKKK), with MAPKs phosphorylating serine/threonine residues on target proteins to control a variety of cellular activitie...

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“…In addition to this transcriptional pathway, progesterone can activate rapid signaling pathways. Ligand-bound PRs can activate several protein kinases involved in growth factor signaling such as MEK MAPK (55). Furthermore, there is evidence that PRs contain a proline-rich motif that can directly interact and active c-Src tyrosine kinases and thereby activate ERK signaling pathway (56).…”

Section: Progesteronementioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

124

147

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Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

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Integration of progesterone receptor action with rapid signaling events in breast cancer models

Cited by 58 publications

References 86 publications

Understanding the regulation of pituitary progesterone receptor expression and phosphorylation

Understanding the regulation of pituitary progesterone receptor expression and phosphorylation

Genomic Collaboration of Estrogen Receptor α and Extracellular Signal-Regulated Kinase 2 in Regulating Gene and Proliferation Programs

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

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