Reviewing the molecular mechanisms which increase endometrial cancer (EC) risk in women with polycystic ovarian syndrome (PCOS): Time for paradigm shift?

Shafiee, Mohamad Nasir; Chapman, Caroline; Abu, Jafaru; Atiomo, William

doi:10.1016/j.ygyno.2013.06.032

Cited by 39 publications

(30 citation statements)

References 31 publications

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“…The exact mechanisms that predispose PCOS women to EC remain unknown. Current hypotheses include a link between obesity and elevated oestrogen levels, inflammation, type 2 diabetes and hyperinsulinaemia . In recently published studies, we found altered expression of genes involved in insulin signalling (IGF‐1, IGFBP1 and PTEN) and lipogenic gene regulation in the endometrium and serum of women with PCOS and EC compared with controls .…”

Section: Introductionmentioning

confidence: 63%

Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome

Atiomo

Shafiee

Chapman

et al. 2017

Clinical Endocrinology

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SummaryObjectiveWomen with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC).AimTo investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC.Design and MethodsPatients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross‐sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study.ResultsWe show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001).ConclusionsThe results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.

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Section: Introductionmentioning

confidence: 63%

Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome

Atiomo

Shafiee

Chapman

et al. 2017

Clinical Endocrinology

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“…Our results, based on only five cases, were consistent with a positive association. The high levels of unopposed estrogens, luteinizing hormone (LH), and insulin and low levels of sex hormone binding globulin (SHGB) found among women with PCOS may all contribute to increased risk [50]. Some prior studies have found a higher risk of endometrial cancer among women with a history of infertility [17,19], while others did not [5,10].…”

Section: Discussionmentioning

confidence: 99%

Reproductive factors and incidence of endometrial cancer in U.S. black women

Sponholtz

Palmer

Rosenberg

et al. 2017

Cancer Causes Control

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Purpose Previous studies have shown that reproductive history is a strong determinant of endometrial cancer risk among white women. Less is known about how reproductive history affects endometrial cancer risk among black women, whose incidence and mortality differ from white women. We investigated the associations of age at menarche, parity, timing of births, and menopausal age with endometrial cancer in the Black Women’s Health Study, a prospective cohort study. Methods Every 2 years from 1995 to 2013, 47,555 participants with intact uteri at baseline in 1995 completed questionnaires on reproductive and medical history, and lifestyle factors. Self-reported cases of endometrial cancer were confirmed by medical record, cancer registry, or death certificate when available. Cox proportional hazards regression was used to estimate multivariable incidence rate ratios (IRR) and 95% confidence intervals (CI). Results During 689,501 person-years of follow-up, we identified 300 incident cases of endometrial cancer. The strongest associations with endometrial cancer were found for early age at menarche (<11 vs. 12–13 years: IRR: 1.82, 95% CI: 1.31, 2.52), and later age at first birth (≥30 vs. <20 years: IRR: 0.26, 95% CI: 0.13, 0.50). Parous women were less likely than nulliparous women to develop endometrial cancer (IRR: 0.77, 95% CI: 0.57, 1.05), but there was little evidence of a dose-response relation for number of births. Conclusion Associations between reproductive factors and endometrial cancer among black women were generally consistent with those in studies of white women.

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“…Insulin levels reduce the amount of IGFBP which in turn increases the amount of circulating IGF. IGF has been shown to induce LH receptors increasing LH levels, again suggesting an interaction between insulin resistance, LH and EC [81]. It should be noted that the triad of obesity, insulin resistance and diabetes in metabolic syndrome carried significant risks of EC [82].…”

Section: Endometrial Carcinoma and Pcosmentioning

confidence: 97%