KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

Yoo, Jeong-Eun; Kim, Tae Hoon; Fazleabas, Asgerally T.; Palomino, Wilder A.; Ahn, Soo Hyun; Tayade, Chandrakant; Schammel, David P.; Young, Steven L.; Jeong, Jae Wook; Lessey, Bruce A.

doi:10.1038/s41598-017-04577-w

Cited by 115 publications

(95 citation statements)

References 78 publications

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“…We expect our data to have external validity, since our results are similar to those published at the SART database. Finally, the BCL6 test has been validated in women with UI and shown previously to be associated with both endometriosis and progesterone resistance (11,18), lending credence to the results obtained.…”

Section: Discussionmentioning

confidence: 52%

“…In addition, inflammation is associated with P-resistance and an immune-regulated impact on the endometrium (39,40). BCL6 pairs with the histone deacetylase SIRT1, is centrally associated with epigenetic alterations in endometrial gene expression associated with endometriosis and likely has multiple effects on other key down-stream progesterone-regulated genes (18). …”

Section: Discussionmentioning

confidence: 99%

“…The over-expression has been associated with increased cellular proliferation (14) and BCL6 is stabilized by STAT3 activation and stimulates cytokine expression, including IL-1, IL-6 and IL-18 (15–17). We recently showed that endometrial BCL6 pairs with a histone deacetylase sirtuin-1 (SIRT1), which is also aberrantly expressed in response to activated KRAS in endometriosis (18). Together, SIRT1/BCL6 complex binds to and inactivates key regulators of progesterone action in the endometrium such as Gli in women with endometriosis.…”

Section: Introductionmentioning

confidence: 99%

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Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Almquist

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Stone

et al. 2017

Fertility and Sterility

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Objective To evaluate endometrial BCL6 expression as a prognostic biomarker for In Vitro Fertilization (IVF) outcome in women with unexplained infertility (UI) prior to embryo transfer. Design Prospective cohort study. Setting University associated infertility clinic. Patients Women with UI for greater than 1 year. Interventions We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed mid-luteal phase biopsy and completed an IVF cycle and embryo transfer. Main Outcome Measure(s) Clinical pregnancy rate (CPR) and live birth rate (LBR) per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an HSCORE (> 1.4). Results Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher CPR (11/17; 64.7%; 95%CI: 41.3 to 82.6), compared to women with abnormal (high) BCL6 expression (9/52; 17.3%; 95%CI: 9.3 to 30.8). These results yield a relative risk (RR) of 0.267 (95%CI: 0.13 to 0.53; p = 0.0004) for those with normal BCL6 expression, an absolute benefit (AB) of 47.4% (95%CI: 22.5 to 72). LBR was also significantly higher in women with low BCL6 expression(10/17; 58.8; 95%CI: 36 to 78.4), compared to women with abnormal BCL6 expression (6/52; 11.5%; 95%CI: 5.4 to 23). The RR was 0.19 (95%CI: 0.08 to 0.45; p = 0.0002), yielding an AB of 47.3% (95%CI: 21.8 to 67.8). Conclusions Aberrant BCL6 expression (> 1.4 HSCORE) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Almquist

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Stone

et al. 2017

Fertility and Sterility

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“…Among other receptivity markers altered in endometriosis are the transcriptional gene repressor BLC6 and the histone deacetylase sirtuin 1 (SIRT1), whose co-expression is promoted by pro-inflammatory environment in eutopic endometrium from endometriosis patients; both are used for the diagnosis of disease. BLC6 and SIRT1 overexpression (induced by Kirsten rat sarcoma viral oncogene, KRAS) alter the actions of P4 by suppression of the promoter of GLI1, a critical mediator of progesterone action in the Indian Hedgehog pathway, contributing to the pathophysiology of this disease and infertility through the increase of P4 resistance (163).…”

Section: Association Of Inflammation With Infertility In Patients Witmentioning

confidence: 99%

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

et al. 2020

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Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue (glands and stroma) outside the uterus, mainly in the peritoneal cavity, ovaries, and intestines. This condition shows estrogen dependency and progesterone resistance, and it has been associated with chronic inflammation, severe pain, and infertility, which negatively affect the quality of life in reproductive women. The molecular mechanisms involved in the pathogenesis of endometriosis are not completely understood; however, inflammation plays a key role in the pathophysiology of the disease, mainly by altering the function of immune cells (macrophages, natural killer, and T cells) and increasing levels of pro-inflammatory mediators in the peritoneal cavity, endometrium, and blood. These immune alterations inhibit apoptotic pathways and promote adhesion and proliferation of endometriotic cells, as well as angiogenesis and neurogenesis in endometriotic lesions. It has been demonstrated that hormonal alterations in endometriosis are related to the inflammatory unbalance in this disease. Particularly, steroid hormones (mainly estradiol) promote the expression and release of pro-inflammatory factors. Excessive inflammation in endometriosis contributes to changes of hormonal regulation by modulating sex steroid receptors expression and increasing aromatase activity. In addition, dysregulation of the inflammasome pathway, mediated by an alteration of cellular responses to steroid hormones, participates in disease progression through preventing cell death, promoting adhesion, invasion, and cell proliferation. Furthermore, inflammation is involved in endometriosis-associated infertility, which alters endometrium receptivity by impairing biochemical responses and decidualization. The purpose of this review is to present current research about the role of inflammasome in the pathogenesis of endometriosis as well as the molecular role of sex hormones in the inflammatory responses in endometriosis.

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“…• EE from women with endometriosis shows coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer throughout the menstrual cycle [125].…”

Section: Krasmentioning

confidence: 99%

How Benign is Endometriosis: Multi-Scale Interrogation of Documented Evidence

Ghosh

Anupa

et al. 2019

COGO

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Endometriosis is an inflammatory disease characterized by the presence of endometrium-like tissue outside the uterus primarily on pelvic organs and tissues. It affects up to 15% of women in the reproductive age group and is often associated with pelvic pain and subfertility. Different theories explain how retrograde menstruation gives rise to endometrial deposits at ectopic sites, and how several other factors are involved in the progression of the disease. Its final diagnosis is established through direct visualization at laparoscopy or surgery followed by histological confirmation. Available epidemiological reports along with histopathological observations and molecular studies shed interesting light on the pathogenetic basis of different variants of the disease like deep infiltrating endometriosis and ovarian endometriosis. Evidence also suggests that endometriosis is a neoplastic condition which serves as a precursor of ovarian and endometrial cancers. In the present review, we have attempted to take a stock of the current epidemiological and molecular knowledge regarding endometriosis associated cancers and develop a model of functional network with interactions among critical genomic factors regulating cellular processes leading to fibrotic reaction. It is being conjectured that cyclic bleeding associated with inflammatory and oxidative stress followed by repeated tissue injury and repair along with recurrent estrogenic stimulation and ovulatory events in the pelvic environment bring about the complex phenotype of atypical endometriosis and associated neoplasm with a trade-off malignant transformation in high risk population. Finally, we have presented an algorithm for pre-emptive monitoring and management of endometriosis-associated cancers.

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KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

Cited by 115 publications

References 78 publications

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

How Benign is Endometriosis: Multi-Scale Interrogation of Documented Evidence

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