Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay, Mostafa A.; Al-Hendy, Ayman; Kılıç, Gökhan; Boehning, Darren

doi:10.2119/molmed.2014.00053

Cited by 128 publications

(176 citation statements)

References 163 publications

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“…Moreover, progesterone receptors have already been described in thyroid follicular cells, and progesterone has been shown to upregulate genes involved in thyroid function and growth on normal human thyroid cells in vitro . Besides, thyroid cancer cells and fibroids are both able to biosynthesize estradiol in situ through the action of aromatase …”

Section: Discussionmentioning

confidence: 99%

Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort

Guenego

Mesrine

Dartois

et al. 2018

Clinical Endocrinology

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Summary Background Thyroid cancers are threefold more frequent in women than in men. A role of reproductive or hormonal factors has been suggested but with contradictory results. We investigated potential associations between history of hysterectomy, with or without oophorectomy, and history of benign gynaecological disease (uterine fibroids, endometriosis) and the incidence of differentiated thyroid cancer, in a large French prospective cohort. Methods A total of 89 340 women from the E3N cohort were followed up between 1990 and 2012. Gynaecological diseases treated by surgery were self‐reported. Thyroid cancers were validated by histological reports. Time‐dependent covariates included smoking status, BMI and history of benign thyroid disease. Cox proportional hazard models with age as timescale were used to estimate Hazard Ratios (HR) and 95% confidence intervals (CI). Results A total of 412 cases of thyroid cancer were diagnosed during follow‐up. A history of hysterectomy was associated with an increased risk of differentiated thyroid cancer (adjusted HR=2.05; 95%CI: 1.65‐2.55). The association was not altered after further adjustment for reproductive factors. Endometriosis, uterine polyps, ovarian cysts and oophorectomy without hysterectomy were not associated with the risk of thyroid cancer. A history of fibroids was also significantly related to the risk of thyroid cancer over the follow‐up period (adjusted HR=1.91; 95%CI: 1.50‐2.44) and the increased risk persisted after adjustment for history of hysterectomy. Conclusions Women who had either a history of fibroids or hysterectomy had an increased risk of differentiated thyroid cancer. These findings suggest shared biological mechanisms between fibroids and thyroid cancer, which deserve to be further dissected.

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Section: Discussionmentioning

confidence: 99%

Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort

Guenego

Mesrine

Dartois

et al. 2018

Clinical Endocrinology

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“…Furthermore, there appears to be an interactive role between gonadal hormones, growth factors, and cytokines that control cell proliferation and ECM production in the growth of leiomyoma tumors (32,50,51).…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Malik

Britten

Cox

et al. 2016

Fertility and Sterility

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This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy.

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“…Furthermore, Lee found that a TGF-β neutralizing antibody attenuated levels of type I and III collagen mRNA in leiomyoma and myometrial cells [21]. Therefore, it is indicated that TGF-β3 is able to stimulate proliferation in both leiomyoma and myometrial cells [23]. TGF-β family members play their roles by binding to cell membrane receptors and by transducing signals.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β signaling pathway cross-talking with ERα signaling pathway on regulating the growth of uterine leiomyoma activated by phenolic environmental estrogens in vitro

Shen

Lü

et al. 2015

Tumor Biol.

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The aim of this paper is to study the participation of transforming growth factor-β (TGF-β) signaling pathway in mediating the growth of human uterine leiomyoma (UL) activated by phenolic environmental estrogens (EEs), via the interaction between TGF-β and ER signaling pathways. The UL cells were prepared by primary culture and subculture methods. To validate the role of TGF-β3 (5 ng/ml) for the viability of human uterine leiomyoma cells, CCK-8 assay was performed in each of five treatment groups including E2 group (E2 10(9) mol/l), BPA group (bisphenol A 10 μmol/l), NP group (nonylphenol 32 μmol/l), OP group (octylphenol 8 μmol/l), or control group (DMSO only). Subsequently, qRT-PCR was applied to detect mRNA expressions of ERα and c-fos, while western blot assay was used to test the expressions of p-Smad3, SnoN, and c-fos proteins in all settings mentioned above; the expressions were compared among different groups, and also in settings with and without synchronous treatment of ICI 182,780. Primarily cultured UL cells were successfully established. Compared with the control group, there were statistically significant increases in the proliferation rate of the UL cells in all EE groups or treated with TGF-β3 only (p < 0.05). Nevertheless, a slight decrease in proliferation rate of UL was detected in coexistence with TGF-β3 in all EE groups (p > 0.05). Interestingly, mRNA expressions of ERα and c-fos reduced in the setting of coexistence of TGF-β3 and EEs compared to isolated EE treatment (p < 0.05). Compared with the control group, the expression of p-Smad3 and c-fos proteins significantly decreased (p < 0.05) in each of E2, BPA, NP, and OP group, and the expression of SnoN protein also significantly reduced only in BPA and NP groups (p < 0.05), followed by TGF-β3 treatment. When adding ICI 182,780, the expression of p-Smad3 protein significantly increased in OP group (p < 0.05), but slightly increased in E2, BPA, NP, and OP groups (p > 0.05). However, compared with the control group, the expressions of SnoN and c-fos proteins significantly decreased (p < 0.05) after adding ICI182,780. Moreover, there was a significant statistical difference in the expression of p-Smad3, SnoN, and c-fos proteins between pre- and post-treatment of ICI 182,780 in all groups (p < 0.05). The ERα signaling pathway and TGF-β signaling pathway have different roles in the control of UL cell proliferation. The phenolic EEs can be a promoter of UL cell proliferation, which is mediated by ERα signaling pathway and its cross-talking with TGF-β signaling pathway. Both less exposure to EEs and blockade of TGF signaling pathway are necessary strategies to prevent UL.

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Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Cited by 128 publications

References 163 publications

Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort

Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones

Transforming growth factor-β signaling pathway cross-talking with ERα signaling pathway on regulating the growth of uterine leiomyoma activated by phenolic environmental estrogens in vitro

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