Polycystic ovary syndrome is causally associated with estrogen receptor–positive instead of estrogen receptor–negative breast cancer: a Mendelian randomization study

Wu, Pengfei; Li, Ruizhuo; Zhang, Wan; Hu, Hui-Yu; Wang, Wei; Lin, Yingsong

doi:10.1016/j.ajog.2020.05.016

Cited by 16 publications

(11 citation statements)

References 5 publications

(15 reference statements)

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“…Hyperandrogenism and insulin resistance may play a role in this association because they are risk factors for both PCOS and breast cancer. Our findings are consistent with a recent study wherein genetically predicted PCOS was associated with estrogen receptor (ER) positive rather than ER negative breast cancer, 6 because luminal A-like, luminal B/ HER2-negative-like, and luminal B-like subtypes are all ER positive and/or progesterone receptor positive. Reassuringly, PCOS does not increase the risk of subtypes that have the worst prognosis (HER2-enriched-like and triple-negative).…”

Section: Discussionsupporting

confidence: 92%

Polycystic ovary syndrome and breast cancer subtypes: a Mendelian randomization study

Zhu

Cui

Goodarzi

2021

American Journal of Obstetrics and Gynecology

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Section: Discussionsupporting

confidence: 92%

Polycystic ovary syndrome and breast cancer subtypes: a Mendelian randomization study

Zhu

Cui

Goodarzi

2021

American Journal of Obstetrics and Gynecology

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“…Nevertheless, at 13.5 months Chk2-/mice have reduced follicle atresia, a higher number of ovulated MII oocytes, and higher AMH levels [70]. In the same study, it was also reported that a CHEK2 loss-of-function allele is associated with later menopausal age in humans [70]. This would be in line with women with PCOS, as they also present with an increased ovarian reserve, higher AMH levels even at later reproductive years, and delayed menopause [5][6][7]9,72].…”

Section: Discussionmentioning

confidence: 96%

“…Nonetheless, the fact that the risks do not seem to translate into clinical findings is notable, and may indicate, for example, more efficient DNA repair systems in women with PCOS, which has also been associated with a later onset of menopause [27,70].…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of Chk2 in mice leads to a maximized ovarian reserve at postnatal day 2 (P2); however, prepubertal (P19) Chk2-/mice have a comparable number of oocytes, and the number of litters and pups per litter are comparable to Chk2+/littermates in adult mice [71]. Nevertheless, at 13.5 months Chk2-/mice have reduced follicle atresia, a higher number of ovulated MII oocytes, and higher AMH levels [70]. In the same study, it was also reported that a CHEK2 loss-of-function allele is associated with later menopausal age in humans [70].…”

Section: Discussionmentioning

confidence: 99%

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Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

Tyrmi

Arffman

Pujol-Gualdo

et al. 2021

Preprint

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Background: Polycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe - Finnish and Estonian - to provide a basis for a new understanding of the genetic determinants of PCOS. Methods and Findings: We conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts. In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 x 10-8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 x 10-16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 x 10-8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16. Conclusions: We identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.

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“…Based on these findings, it may be assumed that loss of ERα in TCs associated with a normal or increased ERβ activity in GCs may lead to the development of PCOS. However, studies on human PCOS tissues only partially support the assumption [ 155 , 156 , 157 , 158 ]. Another ovarian disease that has been linked to estrogen signaling is ovarian cancer [ 159 ].…”

Section: Erβ and Gonadotropins In Ovarian Diseasesmentioning

confidence: 99%

ERβ Regulation of Gonadotropin Responses during Folliculogenesis

Lee

Chakravarthi

Wolfe

et al. 2021

IJMS

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Gonadotropins are essential for regulating ovarian development, steroidogenesis, and gametogenesis. While follicle stimulating hormone (FSH) promotes the development of ovarian follicles, luteinizing hormone (LH) regulates preovulatory maturation of oocytes, ovulation, and formation of corpus luteum. Cognate receptors of FSH and LH are G-protein coupled receptors that predominantly signal through cAMP-dependent and cAMP-independent mechanisms that activate protein kinases. Subsequent vital steps in response to gonadotropins are mediated through activation or inhibition of transcription factors required for follicular gene expression. Estrogen receptors, classical ligand-activated transcriptional regulators, play crucial roles in regulating gonadotropin secretion from the hypothalamic–pituitary axis as well as gonadotropin function in the target organs. In this review, we discuss the role of estrogen receptor β (ERβ) regulating gonadotropin response during folliculogenesis. Ovarian follicles in Erβ knockout (ErβKO) mutant female mice and rats cannot develop beyond the antral state, lack oocyte maturation, and fail to ovulate. Theca cells (TCs) in ovarian follicles express LH receptor, whereas granulosa cells (GCs) express both FSH receptor (FSHR) and LH receptor (LHCGR). As oocytes do not express the gonadotropin receptors, the somatic cells play a crucial role during gonadotropin induced oocyte maturation. Somatic cells also express high levels of estrogen receptors; while TCs express ERα and are involved in steroidogenesis, GCs express ERβ and are involved in both steroidogenesis and folliculogenesis. GCs are the primary site of ERβ-regulated gene expression. We observed that a subset of gonadotropin-induced genes in GCs, which are essential for ovarian follicle development, oocyte maturation and ovulation, are dependent on ERβ. Thus, ERβ plays a vital role in regulating the gonadotropin responses in ovary.

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Polycystic ovary syndrome is causally associated with estrogen receptor–positive instead of estrogen receptor–negative breast cancer: a Mendelian randomization study

Cited by 16 publications

References 5 publications

Polycystic ovary syndrome and breast cancer subtypes: a Mendelian randomization study

Polycystic ovary syndrome and breast cancer subtypes: a Mendelian randomization study

Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

ERβ Regulation of Gonadotropin Responses during Folliculogenesis

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