Chapter 2 Progesterone Receptor Action in Leiomyoma and Endometrial Cancer

Kim, Julie; Sefton, Elizabeth C.; Bulun, Serdar E.

doi:10.1016/s1877-1173(09)87002-6

Cited by 20 publications

(20 citation statements)

References 185 publications

(209 reference statements)

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“…Initially dubbed as "the progesterone hypothesis" (6), the role of progesterone in leiomyoma pathobiology is becoming more established (8,49). Kawaguchi and colleagues (50) demonstrated that mitotic activity in uterine leiomyomas is significantly higher in secretory (progesterone-dominant) phase compared with proliferative (estrogendominant) phase of the menstrual cycle.…”

Section: Progesteronementioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

129

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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Section: Progesteronementioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

129

147

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“…The importance of P 4 has led to the continued development of synthetic progesterone receptor (PR) ligands for a variety of women’s health issues [1,2]. For example, oral contraceptives, combination hormone replacement therapy (HRT) for the treatment of menopausal symptoms, and to reduce the risk of endometrial hyperplasia and cancer associated with unopposed E 2 therapy [3-5].…”

Section: Introductionmentioning

confidence: 99%

Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats

Toh

Mendonca

Eddie

et al. 2013

J Steroids Horm Sci

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Objective Progesterone (P4) plays a central role in women's health. Synthetic progestins are used clinically in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Unfortunately, synthetic progestins are associated with side effects, including cardiovascular disease and breast cancer. Botanical dietary supplements are widely consumed for the alleviation of a variety of gynecological issues, but very few studies have characterized natural compounds in terms of their ability to bind to and activate progesterone receptors (PR). Kaempferol is a flavonoid that functions as a non-steroidal selective progesterone receptor modulator (SPRM) in vitro. This study investigated the molecular and physiological effects of kaempferol in the ovariectomized rat uteri. Methods Since genistein is a phytoestrogen that was previously demonstrated to increase uterine weight and proliferation, the ability of kaempferol to block genistein action in the uterus was investigated. Analyses of proliferation, steroid receptor expression, and induction of well-established PR-regulated targets Areg and Hand2 were completed using histological analysis and qPCR gene induction experiments. In addition, kaempferol in silico binding analysis was completed for PR. The activation of estrogen and androgen receptor signalling was determined in vitro. Results Molecular docking analysis confirmed that kaempferol adopts poses that are consistent with occupying the ligand-binding pocket of PRA. Kaempferol induced expression of PR regulated transcriptional targets in the ovariectomized rat uteri, including Hand2 and Areg. Consistent with progesterone-l ke activity, kaempferol attenuated genistein-induced uterine luminal epithelial proliferation without increasing uterine weight. Kaempferol signalled without down regulating PR expression in vitro and in vivo and without activating estrogen and androgen receptors. Conclusion Taken together, these data suggest that kaempferol is a unique natural PR modulator that activates PR signaling in vitro and in vivo without triggering PR degradation.

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“…Достоверные изменения экспрессии PR-B-изоформы рецептора прогестерона были выявлены лишь в Ki67-негативных лейомиомах, где было отмечено значительное усиление син-теза PR-B. Известно, что именно PR-B-изоформа рецептора прогестерона действует как актива-тор генов, ассоциированных с прогестероном, тогда как PR-A функционирует как ингиби-тор PR-B [11]. Точные механизмы, определяю-щие различную активность двух изоформ PR, полностью не установлены.…”

Section: Discussionunclassified

“…Точные механизмы, определяю-щие различную активность двух изоформ PR, полностью не установлены. Предполагают, что PR-A и PR-B имеют различную конформацию в клетке, что определяет их функциональные различия [11]. Так, PR-A-изоформа не способ-на эффективно рекрутировать коактиваторы рецепторов прогестерона SRc-1 и GRIP1 [12].…”

Section: Discussionunclassified

Molecular mechanisms of regulation of uterine leiomyoma growth

et al. 2017

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Background: to elucidate the molecular mechanisms, regulating growth and proliferation of leiomyoma cells, the estimation of the activity of PR-A and PR-B isoforms of progesterone receptor and PI3K/Akt and MAPК kinases, participating in signal transduction from sex steroids and growth factors, has the special interest. Aim of the work: to investigate the character of the expression of mRNAs of PR-A and PR-B isoforms of progesterone receptor in leiomyomas of different size and different intensity of cellular proliferation, and to elucidate the relationship between the PR-A and PR-B synthesis and activation of PI3K/Akt and MAPК signaling pathways in tumour tissue. Materials and Methods. The examination of the PR-A, PR-B, Akt, PTEN, ERK and Ki67 mRNAs expression in normal myometrium and leiomyoma tissues of 29 women with uterine leiomyoma was performed using RP-PCR. Results. It was found that in general the leiomyoma tissue was characterized by the high level of PR-A, PTEN and ERK mRNAs expression comparing to the miometrium. Distinctive characteristic of the small leiomyomas and leiomyomas with low proliferative activity was the highest synthesis of PR-A isoform of progesterone receptor. In large leiomyomas and in proliferating Ki67+ leiomymas the significant increase of ERK mRNA expression was seen. Conclusion. Activation of the PR-A isoform of progesterone receptor and MAPK/ERK signaling pathway associated with the inhibition of PI3K/Akt signaling due to high synthesis of PTEN plays the important role in mechanisms, regulating leiomyoma growth.

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Chapter 2 Progesterone Receptor Action in Leiomyoma and Endometrial Cancer

Cited by 20 publications

References 185 publications

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats

Molecular mechanisms of regulation of uterine leiomyoma growth

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