
==== Front
World J Surg Oncol
World J Surg Oncol
World Journal of Surgical Oncology
1477-7819
BioMed Central London

3504
10.1186/s12957-024-03504-4
Research
Association of CYP7B1 expression with the prognosis of endometrial cancer: a retrospective study
Lu Xiao-Fang 1
Huang Tao 2
Chen Chang 3
Zhang Jing 1
Fu Xu-Yong 1
Cheng Bo 4
Zhou Ya-Yan 5
Lei Jia leijia33333@sina.com

2
Lu Da-Lin dalinlu@jnu.edu.cn

1
1 grid.258164.c 0000 0004 1790 3548 Department of Epidemiology, School of Medicine, Jinan University, No. 601, Huangpu Avenue West, Tianhe District, Guangzhou, 510632 China
2 https://ror.org/059wqqf58 grid.478120.8 Department of Gynecology, Wuzhou Red Cross Hospital, No. 3-1, Xinxing 1st Road, Wanxiu District, Wuzhou, 543002 China
3 https://ror.org/059wqqf58 grid.478120.8 Department of Pathology, Wuzhou Red Cross Hospital, Wuzhou, China
4 https://ror.org/05tf9r976 grid.488137.1 0000 0001 2267 2324 Department of Pathology, Chinese People’s Liberation Army Rocket Force Characteristic Medical Center, Beijing, China
5 grid.440218.b 0000 0004 1759 7210 Department of Radiation Oncology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
17 9 2024
17 9 2024
2024
22 2519 2 2024
13 8 2024
© The Author(s) 2024
2024
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Background

Endometrial cancer (EC) tissues express CYP7B1, but its association with prognosis needs to be investigated.

Methods

Immunohistochemistry and image analysis software were used to assess CYP7B1 protein expression in paraffin-embedded endometrial tumor sections. Associations between CYP7B1 and clinical factors were tested with the Wilcoxon rank-sum test. Kaplan-Meier curves were employed to describe survival, and differences were assessed using the log-rank test. Cox regression analysis was used to assess the association between CYP7B1 expression and the prognosis of patients with EC.

Results

A total of 307 patients were enrolled with an average age of 52.6 ± 8.0 years at diagnosis. During the period of follow-up, 46 patients (15.0%) died, and 29 (9.4%) suffered recurrence. The expression of CYP7B1 protein is significantly higher in the cytoplasm than in the nucleus (P < 0.001). Patients aged < 55 years (P = 0.040), ER-positive patients (P = 0.028) and PR-positive patients (P < 0.001) report higher levels of CYP7B1 protein. Both univariate (HR = 0.41, 95% CI: 0.18–0.90, P = 0.025) and multivariate (HR = 0.35, 95%CI:0.16–0.79, P = 0.011) Cox regression analyses demonstrate that high CYP7B1 protein expression predicts longer overall survival (OS). When considering only ER-positive patients (n = 265), CYP7B1 protein expression is more strongly associated with OS (HR = 0.20,95%CI:0.08–0.52, P = 0.001). The 3-year OS and 5-year OS in the low-CYP7B1 subgroup are 81.6% and 76.8%, respectively; while in the high-CYP7B1 subgroup are 93.0% and 92.0%, respectively (P = 0.021).

Conclusions

High CYP7B1 protein expression predicted longer OS, suggesting that it may serve as an important molecular marker for EC prognosis.

Keywords

Endometrial cancer
Estrogen receptor
CYP7B1
Overall survival
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82003522 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Endometrial cancer (EC) is one of the most prevalent gynecological malignancies [1]. Immunotherapy, particularly immune checkpoint inhibitors, has made significant advances in the treatment of EC [2, 3]. The incidence of EC is on the rise with the increasing rate of obesity [4]. Studies have discovered a positive correlation between the cholesterol intake and the risk of EC [5, 6]. Notably, obesity promotes the synthesis of cholesterol in the body [7–11]. As a major metabolite of cholesterol, 27-Hydroxycholesterol (27HC) is the most abundant circulating oxysterol, and its plasma levels are strongly linked to cholesterol levels [12]. It was shown that 27HC, the first endogenous selective estrogen receptor modulator (SERM) to be discovered, increases the risk of EC development and progression by stimulating epithelial cell proliferation through an estrogen receptor (ER) dependent pathway [13, 14].

Two crucial enzymes determine the content of 27HC: cytochrome P450 oxidase (CYP27A1), which catalyzes the synthesis, and oxysterol 7α-hydroxylase (CYP7B1), which is accountable for breakdown [15, 16]. CYP7B1 contains 6 exons and 5 introns, with the gene’s coding length being a minimum of 65 kb [17]. Compared to CYP7B1+/+ mice, CYP7B1−/− mice had a significantly shorter tumor latency [18]. Reduced CYP7B1 expression in ER-positive breast tumors resulted in the accumulation of 27HC in tumors, which was linked to lower overall survival (OS) [19]. High CYP7B1 expression was correlated with longer progression-free survival in patients with ovarian cancer [20]. These studies indicate that CYP7B1 serves as an important biomarker for cancer progression and survival. Despite evidence in other types of cancer, the association between CYP7B1 and EC has not been established.

Therefore, we aimed to evaluate the prognostic value of CYP7B1 protein in patients with EC.

Materials and methods

Patients

Patients diagnosed with EC at Wuzhou Red Cross Hospital between January 2009 and December 2020 were retrospectively studied. The Ethics Committee of Jinan University and Wuzhou Red Cross Hospital have approved this work (Ethics approval number: LL2022-160). This study was based on the patient’s prior written informed consent. The inclusion criteria were: (1) patients with initial surgery; (2) patients older than 18 years; (3) patients with primary EC. The exclusion criteria were as follows: (1) failed to undergo surgery; (2) patients with other malignancies; (3) patients diagnosed with endometrial carcinosarcoma; (4) unavailable tumor tissue sections; (5) lost to follow-up.

Follow up

Patients were followed up by reviewing medical records and conducting telephone interviews. Data were collected until death or September 2022. OS was defined as the period from the surgery to either the time of death or the time of the last follow-up. Recurrence-free survival (RFS) was defined as the duration between surgery and either recurrence or the last follow-up.

Immunohistochemistry

The Department of Pathology provided the paraffin-embedded sections of EC tissues needed for this study. The tissue sections underwent immunohistochemical staining before the quantitative measurement of CYP7B1. Briefly, paraffin sections were first dewaxed and hydrated. Sections were subjected to microwave antigen repair with sodium citrate retrieval solution at pH 6.0, cooled and then treated with 3% H2O2 for 10 min to block endogenous peroxidase activity. Next, sections were incubated with rabbit anti-human CYP7B1 antibody (primary antibody) at 4 °C for 17 h and with the goat anti-rabbit lgG antibody (secondary antibody) at 37 °C for 20 min (all purchase from Yong Jin Biotech). 3,3’-diaminobenzidine (DAB) was used for color development and hematoxylin was used for redyeing. Finally, the sections were sealed with neutral balsam.

Detection of CYP7B1 expression via image analysis

Positive expression was determined by the presence of brown-yellow granules in the nucleus/cytoplasm of EC. All sections were photographed using a microscope under the same conditions. All photographs were processed and analyzed using image analysis software Image-Pro Plus 7.2. Measurement data for relevant indicators was obtained for statistical analysis. Briefly, new images were added to the software, and an optical density correction was performed. The desired depiction tool was used to select the measurement area and the color parameters were adjusted. The measurement indicators to be selected included the integral optical density (IOD) and the total area of the measurement area (Area). The software was run to obtain the raw data of the measurement indicators. The IOD/Area ratio, which is the average optical density (AOD), was calculated. The AOD was then statistically analyzed.

Statistical analyses

All immunohistochemical images were analyzed by Image-Pro Plus 7.2 and statistically analyzed using AOD values. Continuous variables were represented by means and standard deviations, while categorical variables were summarized by frequencies and percentages. The Wilcoxon rank sum test was applied to assess correlations between binary categorical variables and CYP7B1 expression data. The surv_cutpoint function was used to obtain the optimal cut-off value for CYP7B1 [21]. Univariate and multivariate Cox regression analyses were conducted to evaluate the association between CYP7B1 expression and the prognosis of EC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. Kaplan-Meier curves were used to describe OS and RFS, and the log-rank test was used to compare survival differences. Statistical analyses were performed using R software (version 4.2.2). A two-tailed P value < 0.05 was considered statistically significant.

Results

Clinicopathological characteristics

Of the 353 patients with EC, 307 patients who conformed to the inclusion and exclusion criteria were finally enrolled in this study (Fig. 1). The average age of patients at diagnosis was 52.6 ± 8.0 years. 46 patients (15.0%) died, and 29 (9.4%) experienced recurrence. The median follow-up times for OS and RFS were 5.0 (range 0.7–13.6) years and 4.4 (range 0.3–13.6) years, respectively. Patients were divided into FIGO stage I (65.5%), stage II (19.5%), stage III (14.0%) and stage IV (1.0%). More detailed information is shown in Table 1.

Fig. 1 A flow chart describing the process applied to identify the eligible patients to be enrolled in the study

Table 1 Clinicopathological characteristics of the patients

Characteristics	Patients(n = 307)	
Age (years)		
 Mean ± SD	52.6 ± 8.0	
BMI (kg/m2)		
 Mean ± SD	24.1 ± 3.5	
Menopausal status, n (%)		
 Premenopausal	156(50.8)	
 Postmenopausal	151(49.2)	
Histological type, n (%)		
 Type I	281(91.5)	
 Type II	26(8.5)	
FIGO stage, n (%)		
 I	201(65.5)	
 II	60(19.5)	
 III	43(14.0)	
 IV	3(1.0)	
Histological grade, n (%)		
 1	37(12.0)	
 2	151(49.2)	
 3	119(38.8)	
Myometrial infiltration, n (%)		
 ≤ 1/2	224(73.0)	
 > 1/2	83(27.0)	
ER, n (%)		
 Negative	42(13.7)	
 Positive	265(86.3)	
PR, n (%)		
 Negative	52(16.9)	
 Positive	255(83.1)	
Abbreviations BMI, body mass index; ER, estrogen receptor; FIGO, International Federation of Gynecology and Obstetrics; PR, progesterone receptor; SD, standard deviation

Correlations between clinical factors and CYP7B1

A representative image of CYP7B1 expression is shown in Fig. 2A. The result shows that CYP7B1 protein is expressed in both the cytoplasm and the nucleus, with significantly higher expression in the cytoplasm than in the nucleus (P < 0.001, Fig. 2B). CYP7B1 protein expression is reduced in women aged ≥ 55 years compared with in those aged < 55 years. CYP7B1 expression is positively correlated with both ER and PR expression. ER-positive (P = 0.028) and PR-positive (P < 0.001) patients tend to express higher levels of CYP7B1 protein (Table 2).

Fig. 2 CYP7B1 protein expression in endometrial cancer tissues (A) A representative image of CYP7B1 expression. (B) Comparison of CYP7B1 protein expression in cytoplasm and nucleus. Abbreviations AOD, average optical density

Table 2 Relationship between the expression of CYP7B1 and clinicopathological characteristics

	N	CYP7B1 protein	P	
median	interquartile	
Age (years)					
 < 55	192	0.107	0.011–0.281	0.040	
 ≥ 55	115	0.043	0.003–0.265		
BMI (kg/m2)					
 < 25	192	0.077	0.010–0.278	0.796	
 ≥ 25	115	0.106	0.006–0.267		
Menopausal status					
 Premenopausal	156	0.108	0.101–0.278	0.200	
 Postmenopausal	151	0.058	0.005–0.270		
Histological type					
 Type I	281	0.085	0.009–0.277	0.468	
 Type II	26	0.066	0.005–0.231		
FIGO stage					
 I-II	261	0.080	0.009–0.277	0.965	
 III- IV	46	0.098	0.010–0.252		
Histological grade					
 1–2	188	0.092	0.007–0.269	0.727	
 3	119	0.068	0.010–0.284		
Myometrial infiltration					
 ≤ 1/2	224	0.087	0.009–0.278	0.906	
 > 1/2	83	0.074	0.007–0.254		
ER					
 Negative	42	0.032	0.004–0.135	0.028	
 Positive	265	0.102	0.009–0.289		
PR					
 Negative	52	0.014	0.004–0.081	< 0.001	
 Positive	255	0.120	0.010–0.296		
Abbreviations BMI, body mass index; ER, estrogen receptor; FIGO, International Federation of Gynecology and Obstetrics; LNM, lymph node metastasis, LVSI, lymph-vascular space involvement; PR, progesterone receptor

Associations of CYP7B1 levels with patient outcomes

The optimal cut-off value for CYP7B1 protein is determined to be 0.0040 using the surv_cutpoint function of the R package survminer in the R programming language, which effectively separates the expression of the CYP7B1 protein into two distinct groups: low-CYP7B1 and high-CYP7B1.

Univariate Cox regression analysis reveals that high CYP7B1 expression is associated with longer OS (HR = 0.41, 95% CI: 0.18–0.90, P = 0.025) as presented in Table 3. Furthermore, multivariate Cox regression analysis shows that high CYP7B1 expression is an independent prognostic factor for OS, eliminating the effects of other factors (HR = 0.35, 95%CI:0.16–0.79, P = 0.011) as presented in Table 4. When only ER-positive patients are considered, this association persists (HR = 0.20, 95%CI:0.08–0.52, P = 0.001) as presented in Table 4. The beneficial effect of high CYP7B1 expression on ER-positive tumors appears to be more significant for women aged ≥ 55 years (HR = 0.13, 95%CI:0.03–0.59, P = 0.009) as seen in Table 4. Interestingly, high CYP7B1 expression extends OS in postmenopausal ER-positive patients (HR = 0.11, 95%CI:0.03–0.46, P = 0.003) but did not influence OS in premenopausal patients (HR = 0.43, 95%CI:0.07–2.52, P = 0.349) as seen in Table 4. Nevertheless, both univariate (HR = 0.80, 95%CI: 0.38–1.65, P = 0.540) and multivariate (HR = 0.83, 95%CI: 0.37–1.86, P = 0.647) analyses show no significant difference in RFS between the high-CYP7B1 group and the low-CYP7B1 group as seen in Tables 3 and 4. A statistically significant association between CYP7B1 and RFS (HR = 0.50, 95%CI: 0.10–1.27, P = 0.144) is still not found when only ER-positive patients are taken into account. When further stratifying ER-positive patients according to age and menopausal status, the difference in RFS between the high-CYP7B1 and low-CYP7B1 groups is still not statistically significant (P > 0.05) as presented in Table 4.

Table 3 The univariate COX regression analysis of factors predicting OS and RFS of endometrial cancer

	OS	RFS	
HR (95%CI)	P	HR (95%CI)	P	
Age (years)					
 ≥ 55 vs. <55	1.78(0.86–3.70)	0.121	1.58(0.8802.83)	0.123	
BMI (kg/m2)					
 ≥ 25 vs.<25	0.90(0.42–1.94)	0.787	0.90(0.49–1.66)	0.739	
Menopausal status					
 Postmenopausal vs. Premenopausal	1.62(0.77–3.39)	0.203	1.47(0.82–2.63)	0.197	
Histological type					
 Type II vs. Type I	4.00(1.71–9.37)	0.001	3.15(1.52–6.52)	0.002	
FIGO stage					
 III- IV vs. I-II	6.91(3.33–14.33)	< 0.001	6.88(3.85–12.31)	< 0.001	
Histological grade					
 3 vs. 1–2	3.98(1.76–8.99)	< 0.001	4.11(2.16–7.81)	< 0.001	
Myometrial infiltration					
 > 1/2 vs. ≤1/2	5.65(2.63–12.16)	< 0.001	6.78(3.66–12.57)	< 0.001	
ER					
 Positive vs. Negative	0.32(0.15–0.71)	0.005	0.51(0.25–1.02)	0.057	
PR					
 Positive vs. Negative	0.31(0.14–0.65)	0.002	0.42(0.22–0.78)	0.006	
CYP7B1					
 High vs. Low	0.41(0.18–0.90)	0.025	0.80(0.38–1.65)	0.540	
Abbreviations BMI, body mass index; ER, estrogen receptor; FIGO, International Federation of Gynecology and Obstetrics; OS, overall survival; PR, progesterone receptor

Table 4 Multivariate COX regression analysis of associations between CYP7B1 and OS and RFS

	OS_CYP7B1 (Ref. Low)	RFS_ CYP7B1 (Ref. Low)	
HR (95%CI)	P	HR (95%CI)	P	
All patients (n = 307)	0.35(0.16–0.79)	0.011	0.83(0.37–1.86)	0.647	
ER positive patients (n = 265)	0.20(0.08–0.52)	0.001	0.50(0.10–1.27)	0.144	
ER positive/ <55 years (n = 170)	0.16(0.04–0.67)	0.012	0.63(0.17–2.39)	0.499	
ER positive/ ≥55 years (n = 95)	0.13(0.03–0.59)	0.009	0.35(0.09–1.38)	0.134	
ER positive/ Premenopausal (n = 139)	0.43(0.07–2.52)	0.349	1.02(0.18–5.60)	0.985	
ER positive/ Postmenopausal (n = 126)	0.11(0.03–0.46)	0.003	0.33(0.10–1.13)	0.076	
Adjusted for age, BMI, menopausal status; histological type, FIGO stage, histological grade, myometrial infiltration, ER and PR where applicable

Abbreviations ER, estrogen receptor; OS, overall survival; Ref, reference; RFS, recurrence-free survival

Kaplan-Meier curves of CYP7B1 protein expression show that the 3-year OS is 81.6% (95%CI:69.8–93.3) in the low-CYP7B1 subgroup and 93.0% (95%CI:89.8–96.2) in the high-CYP7B1 subgroup. The 5-year OS is 76.8% (95%CI:62.4–91.1) in the low-CYP7B1 subgroup and 92.0% (95%CI:88.5–95.5) in the high-CYP7B1 subgroup (P = 0.021, Fig. 3A). On the other hand, the 3-year RFS presents as 82.3% (95%CI:71.4–93.2) and 87.7% (95%CI:83.6–91.8), respectively. The 5-year RFS is 82.3% (95%CI:71.4–93.2) in the subgroup of patients with low CYP7B1and 84.5% (95%CI:79.8–89.2) in the subgroup of patients with high CYP7B1 (Fig. 3B). However, the difference in 3-year RFS between the low-CYP7B1 and high-CYP7B1 groups is not statistically significant, nor is the difference in 5-year RFS (P = 0.539).

Fig. 3 Kaplan-Meier survival curves of different CYP7B1 expression groups. (A) Overall survival in different CYP7B1 expression groups. (B) Recurrence-free survival in different CYP7B1 expression groups

Discussion

Considering the etiology of estrogen-mediated EC, the role of 27HC remains a significant area of research [22–25]. 27HC has been shown to be linked with growth and progression in cancer [18–20]. CYP7B1 is the enzyme responsible for the breakdown of 27HC. Hypermethylation of the CYP7B1 promoter leads to an elevated 27HC concentration, which promotes the proliferation of ER-positive breast cancer cell [26]. However, there are few studies on the relationship between CYP7B1 and EC [14, 27]. Therefore, it is important to evaluate whether CYP7B1 can be used as a prognostic indicator for patients with EC.

We have gathered new evidence regarding the expression of CYP7B1, the enzyme required for breaking down 27HC. Our findings show that CYP7B1 protein is detected in EC tissues, with notably higher levels in the cytoplasm compared to the nucleus. The expression level of CYP7B1 protein in PR-positive tumors is higher than that in PR-negative tumors. These findings appear to parallel those reported for breast cancer, where a higher proportion of PR-positive tumors was observed in CYP7B1-positive tumors compared to CYP7B1-negative tumors [28]. Furthermore, the present study shows that CYP7B1 protein expression decreases as age increases, suggesting that 27HC accumulation may occure in older patients. A significant positive correlation has been reported between the circulating levels of 27HC and cholesterol, and plasma 27HC levels tend to rise with hypercholesterolemia [19, 29, 30]. Research on breast cancer revealed that the rise of 27HC in tumors was caused by a decrease in CYP7B1 expression [19].

Given the role of CYP7B1 in 27HC metabolism, we proposed that CYP7B1 may influence the outcomes of EC. Our study confirms that CYP7B1 protein expression is an independent predictor of OS, with higher OS in the high-CYP7B1 group compared to the low-CYP7B1 group. Consistent with our results, previous studies have shown that CYP7B1 mRNA expression was downregulated in EC tissues compared to normal tissues, and its expression level was markedly lower in poorly differentiated cancers than in moderately differentiated cancers [14, 27]. ER regulates many physiological functions and plays a crucial role in the development of various types of tumors [31–34]. The absence of ER significantly correlated with advanced stage and higher grade, hence the poor outcome of EC, while its high expression served as a predictor of a better prognosis [35–38]. The present study discovers higher levels of CYP7B1 protein in ER-positive tumors. The results of subgroup analyses of ER-positive patients still support a favorable association between high CYP7B1 protein expression and OS. Interestingly, CYP7B1 protein is more protective in patients aged ≥ 55 years compared to ER-positive patients aged < 55 years. Furthermore, the protective effect of CYP7B1 protein seems to be limited to postmenopausal ER-positive patients. The association between CYP7B1 and prognosis varies in different subgroups, which may be related to the levels of estrogen. Estrogen levels decrease significantly, and serum 27HC increases in postmenopausal women [29, 39]. The promoter of CYP7B1 contains putative response elements for half palindromic hormone response elements (HREs) in the nucleotide sequence from − 738 to − 758 [17]. Estrogen up-regulates CYP7B1, a target gene for estrogen-mediated regulation [40, 41]. Estrogen has contrary effects on CYP7B1 due to ER status [42]. Estradiol stimulates the catalytic activity and mRNA expression of CYP7B1 when ER is present. On the contrary, estradiol inhibits CYP7B1 activity when ER is absent. Tang et al. have explored the mechanism by which estrogen mediates the regulation of the CYP7B1 gene promoter [41]. However, CYP7B1 expression varies in different cancer tissues. In prostate cancer, local methylation of the CYP7B1 promoter leads to increased expression of the CYP7B1 gene [43]. In contrary, increased methylation of the CYP7B1 promoter in breast cancer cells downregulates its expression [26]. Therefore, more research is required to clarify the precise mechanisms of CYP7B1 in EC.

Our research has some noteworthy limitations. Firstly, the retrospective nature of our study restricts our conclusions to associations rather than causal relationships, and the influence from selection bias cannot have been ruled out. Secondly, this study was conducted at a single center and had a relatively small sample size, which limits the generalizability of our findings. Therefore, future large multicentric well-conducted studies are necessary.

Conclusion

In summary, our results supported that CYP7B1 is an independent predictor of EC survival, especially ER-positive EC, suggesting that CYP7B1 may serve as a predictor of EC follow-up.

Acknowledgements

We sincerely thank Disorn Sookthai and Tong-Cun Zhang for helpful discussions on statistics and tumor biology.

Author contributions

Study conception and design: all authors. Data collection: X-FL, TH, CC and JL. Data analysis: X-FL, JZ and X-YF. Drafting the manuscript: X-FL and D-LL. Project supervision: BC, Y-YZ, JL, and D-LL. D-LL and JL are the co-corresponding authors. All authors have reviewed and approved the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant number: 82003522).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This study was approved by Jinan University and Wuzhou Red Cross Hospital Ethics Committee and all patients provided informed consent for the use of their clinical information.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiao-Fang Lu and Tao Huang contributed equally to this work.
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References

1. Sung H Ferlay J Siegel RL Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries CA Cancer J Clin 2021 71 3 209 49 33538338
Sung H, Ferlay J, Siegel RL, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.33538338
2. Oaknin A Bosse TJ Creutzberg CL Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up Ann Oncol 2022 33 9 860 77 35690222
Oaknin A, Bosse TJ, Creutzberg CL, et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(9):860–77.35690222
3. De Felice F Marchetti C Tombolini V Panici PB Immune check-point in endometrial cancer Int J Clin Oncol 2019 24 8 910 6 31049759
De Felice F, Marchetti C, Tombolini V, Panici PB. Immune check-point in endometrial cancer. Int J Clin Oncol. 2019;24(8):910–6.31049759
4. Onstad MA Schmandt RE Lu KH Addressing the role of obesity in Endometrial Cancer Risk, Prevention, and treatment J Clin Oncol 2016 34 35 4225 30 27903150
Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in Endometrial Cancer Risk, Prevention, and treatment. J Clin Oncol. 2016;34(35):4225–30.27903150
5. Gong TT Li D Wu QJ Wang YZ Cholesterol consumption and risk of endometrial cancer: a systematic review and dose-response meta-analysis of observational studies Oncotarget 2016 7 13 16996 7008 26959738
Gong TT, Li D, Wu QJ, Wang YZ. Cholesterol consumption and risk of endometrial cancer: a systematic review and dose-response meta-analysis of observational studies. Oncotarget. 2016;7(13):16996–7008.26959738
6. Biel RK Csizmadi I Cook LS Courneya KS Magliocco AM Friedenreich CM Risk of endometrial cancer in relation to individual nutrients from diet and supplements Public Health Nutr 2011 14 11 1948 60 21752313
Biel RK, Csizmadi I, Cook LS, Courneya KS, Magliocco AM, Friedenreich CM. Risk of endometrial cancer in relation to individual nutrients from diet and supplements. Public Health Nutr. 2011;14(11):1948–60.21752313
7. Miettinen TA Cholesterol production in obesity Circulation 1971 44 5 842 50 5115077
Miettinen TA. Cholesterol production in obesity. Circulation. 1971;44(5):842–50.5115077
8. Mc Auley MT Effects of obesity on cholesterol metabolism and its implications for healthy ageing Nutr Res Rev 2020 33 1 121 33 31983354
Mc Auley MT. Effects of obesity on cholesterol metabolism and its implications for healthy ageing. Nutr Res Rev. 2020;33(1):121–33.31983354
9. Bray GA Medical consequences of obesity J Clin Endocrinol Metab 2004 89 6 2583 9 15181027
Bray GA. Medical consequences of obesity. J Clin Endocrinol Metab. 2004;89(6):2583–9.15181027
10. Feingold KR. Obesity and dyslipidemia. [Updated 2023 Jun 19]. In: Feingold KR, Anawalt B, Blackman MR, et al. editors. Endotext [Internet]. South Dartmouth (MA). MDText.com, Inc.; 2000-.
11. Franssen R Monajemi H Stroes ES Kastelein JJ Obesity and dyslipidemia Med Clin North Am 2011 95 5 893 902 21855698
Franssen R, Monajemi H, Stroes ES, Kastelein JJ. Obesity and dyslipidemia. Med Clin North Am. 2011;95(5):893–902.21855698
12. Karuna R Holleboom AG Motazacker MM Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism Atherosclerosis 2011 214 2 448 55 21130455
Karuna R, Holleboom AG, Motazacker MM, et al. Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism. Atherosclerosis. 2011;214(2):448–55.21130455
13. DuSell CD Umetani M Shaul PW Mangelsdorf DJ McDonnell DP 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator Mol Endocrinol 2008 22 1 65 77 17872378
DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP. 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol. 2008;22(1):65–77.17872378
14. Gibson DA Collins F Cousins FL Esnal Zufiaurre A Saunders PTK The impact of 27-hydroxycholesterol on endometrial cancer proliferation Endocr Relat Cancer 2018 25 4 381 91 29371332
Gibson DA, Collins F, Cousins FL, Esnal Zufiaurre A, Saunders PTK. The impact of 27-hydroxycholesterol on endometrial cancer proliferation. Endocr Relat Cancer. 2018;25(4):381–91.29371332
15. Abdalkareem Jasim S Kzar HH Haider Hamad M The emerging role of 27-hydroxycholesterol in cancer development and progression: an update Int Immunopharmacol 2022 110 109074 35978522
Abdalkareem Jasim S, Kzar HH, Haider Hamad M, et al. The emerging role of 27-hydroxycholesterol in cancer development and progression: an update. Int Immunopharmacol. 2022;110:109074.35978522
16. Starkey NJE Li Y Drenkhahn-Weinaug SK Liu J Lubahn DB 27-Hydroxycholesterol is an estrogen receptor β-Selective negative allosteric modifier of 17β-Estradiol binding Endocrinology 2018 159 5 1972 81 29579190
Starkey NJE, Li Y, Drenkhahn-Weinaug SK, Liu J, Lubahn DB. 27-Hydroxycholesterol is an estrogen receptor β-Selective negative allosteric modifier of 17β-Estradiol binding. Endocrinology. 2018;159(5):1972–81.29579190
17. Wu Z Martin KO Javitt NB Chiang JY Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene CYP7B1 J Lipid Res 1999 40 12 2195 203 10588945
Wu Z, Martin KO, Javitt NB, Chiang JY. Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene CYP7B1. J Lipid Res. 1999;40(12):2195–203.10588945
18. Nelson ER Wardell SE Jasper JS 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology Science 2013 342 6162 1094 8 24288332
Nelson ER, Wardell SE, Jasper JS, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science. 2013;342(6162):1094–8.24288332
19. Wu Q Ishikawa T Sirianni R 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth Cell Rep 2013 5 3 637 45 24210818
Wu Q, Ishikawa T, Sirianni R, et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 2013;5(3):637–45.24210818
20. He S Ma L Baek AE Host CYP27A1 expression is essential for ovarian cancer progression Endocr Relat Cancer 2019 26 7 659 75 31048561
He S, Ma L, Baek AE, et al. Host CYP27A1 expression is essential for ovarian cancer progression. Endocr Relat Cancer. 2019;26(7):659–75.31048561
21. Wang P Yuan D Zhang C High fibrinogen-to-albumin ratio with type 2 diabetes mellitus is associated with poor prognosis in patients undergoing percutaneous coronary intervention: 5-year findings from a large cohort Cardiovasc Diabetol 2022 21 1 46 35313877
Wang P, Yuan D, Zhang C, et al. High fibrinogen-to-albumin ratio with type 2 diabetes mellitus is associated with poor prognosis in patients undergoing percutaneous coronary intervention: 5-year findings from a large cohort. Cardiovasc Diabetol. 2022;21(1):46.35313877
22. Rodriguez AC Blanchard Z Maurer KA Gertz J Estrogen Signaling in Endometrial Cancer: a key oncogenic pathway with several open questions Horm Cancer 2019 10 2–3 51 63 30712080
Rodriguez AC, Blanchard Z, Maurer KA, Gertz J. Estrogen Signaling in Endometrial Cancer: a key oncogenic pathway with several open questions. Horm Cancer. 2019;10(2–3):51–63.30712080
23. Carlson MJ Thiel KW Leslie KK Past, present, and future of hormonal therapy in recurrent endometrial cancer Int J Womens Health 2014 6 429 35 24833920
Carlson MJ, Thiel KW, Leslie KK. Past, present, and future of hormonal therapy in recurrent endometrial cancer. Int J Womens Health. 2014;6:429–35.24833920
24. Chlebowski RT, Anderson GL, Sarto GE et al. Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women’s Health Initiative Randomized Trial. J Natl Cancer Inst 2016;108(3).
25. Dallal CM Lacey JV Jr Pfeiffer RM Estrogen Metabolism and risk of postmenopausal endometrial and ovarian Cancer: the B ∼ FIT cohort Horm Cancer 2016 7 1 49 64 26728471
Dallal CM, Lacey JV Jr., Pfeiffer RM, et al. Estrogen Metabolism and risk of postmenopausal endometrial and ovarian Cancer: the B ∼ FIT cohort. Horm Cancer. 2016;7(1):49–64.26728471
26. Shi SZ Lee EJ Lin YJ Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer Am J Cancer Res 2019 9 10 2194 208 31720082
Shi SZ, Lee EJ, Lin YJ, et al. Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer. Am J Cancer Res. 2019;9(10):2194–208.31720082
27. Tan X Liu S Yao L Cui G Liu J Ding J Comprehensive Analysis of a novel lipid metabolism-related gene signature for Predicting the Prognosis and Immune Landscape in Uterine Corpus Endometrial Carcinoma J Oncol 2022 2022 8028825 35190739
Tan X, Liu S, Yao L, Cui G, Liu J, Ding J. Comprehensive Analysis of a novel lipid metabolism-related gene signature for Predicting the Prognosis and Immune Landscape in Uterine Corpus Endometrial Carcinoma. J Oncol. 2022;2022:8028825.35190739
28. Le Cornet C Walter B Sookthai D Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort Breast Cancer Res 2020 22 1 23 32075687
Le Cornet C, Walter B, Sookthai D, et al. Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort. Breast Cancer Res. 2020;22(1):23.32075687
29. Burkard I von Eckardstein A Waeber G Vollenweider P Rentsch KM Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers Atherosclerosis 2007 194 1 71 8 17107679
Burkard I, von Eckardstein A, Waeber G, Vollenweider P, Rentsch KM. Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers. Atherosclerosis. 2007;194(1):71–8.17107679
30. Kimbung S Chang CY Bendahl PO Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer Endocr Relat Cancer 2017 24 7 339 49 28442559
Kimbung S, Chang CY, Bendahl PO, et al. Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer. Endocr Relat Cancer. 2017;24(7):339–49.28442559
31. Raza S Meyer M Goodyear C Hammer KDP Guo B Ghribi O The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells Cancer Cell Int 2017 17 52 28503095
Raza S, Meyer M, Goodyear C, Hammer KDP, Guo B, Ghribi O. The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells. Cancer Cell Int. 2017;17:52.28503095
32. Althuis MD Fergenbaum JH Garcia-Closas M Brinton LA Madigan MP Sherman ME Etiology of hormone receptor-defined breast cancer: a systematic review of the literature Cancer Epidemiol Biomarkers Prev 2004 13 10 1558 68 15466970
Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME. Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev. 2004;13(10):1558–68.15466970
33. Siegfried JM Hershberger PA Stabile LP Estrogen receptor signaling in lung cancer Semin Oncol 2009 36 6 524 31 19995644
Siegfried JM, Hershberger PA, Stabile LP. Estrogen receptor signaling in lung cancer. Semin Oncol. 2009;36(6):524–31.19995644
34. Liu J Sareddy GR Zhou M Differential effects of Estrogen Receptor β isoforms on Glioblastoma Progression Cancer Res 2018 78 12 3176 89 29661831
Liu J, Sareddy GR, Zhou M, et al. Differential effects of Estrogen Receptor β isoforms on Glioblastoma Progression. Cancer Res. 2018;78(12):3176–89.29661831
35. Van Weelden WJ Reijnen C Küsters-Vandevelde HVN The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study Hum Pathol 2021 109 80 91 33338506
Van Weelden WJ, Reijnen C, Küsters-Vandevelde HVN, et al. The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study. Hum Pathol. 2021;109:80–91.33338506
36. Ren S Wu J Yin W Researches on the correlation between estrogen and progesterone receptors expression and disease-free survival of Endometrial Cancer Cancer Manag Res 2020 12 12635 47 33335423
Ren S, Wu J, Yin W, et al. Researches on the correlation between estrogen and progesterone receptors expression and disease-free survival of Endometrial Cancer. Cancer Manag Res. 2020;12:12635–47.33335423
37. Smith D Stewart CJR Clarke EM ER and PR expression and survival after endometrial cancer Gynecol Oncol 2018 148 2 258 66 29217139
Smith D, Stewart CJR, Clarke EM, et al. ER and PR expression and survival after endometrial cancer. Gynecol Oncol. 2018;148(2):258–66.29217139
38. Backes FJ Walker CJ Goodfellow PJ Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer Gynecol Oncol 2016 141 2 312 7 26957478
Backes FJ, Walker CJ, Goodfellow PJ, et al. Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer. Gynecol Oncol. 2016;141(2):312–7.26957478
39. Shin YA Lee KY Low estrogen levels and obesity are associated with shorter telomere lengths in pre- and postmenopausal women J Exerc Rehabil 2016 12 3 238 46 27419121
Shin YA, Lee KY. Low estrogen levels and obesity are associated with shorter telomere lengths in pre- and postmenopausal women. J Exerc Rehabil. 2016;12(3):238–46.27419121
40. Yamamoto Y Moore R Hess HA Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity J Biol Chem 2006 281 24 16625 31 16606610
Yamamoto Y, Moore R, Hess HA, et al. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem. 2006;281(24):16625–31.16606610
41. Tang W Pettersson H Norlin M Involvement of the PI3K/Akt pathway in estrogen-mediated regulation of human CYP7B1: identification of CYP7B1 as a novel target for PI3K/Akt and MAPK signalling J Steroid Biochem Mol Biol 2008 112 1–3 63 73 18790053
Tang W, Pettersson H, Norlin M. Involvement of the PI3K/Akt pathway in estrogen-mediated regulation of human CYP7B1: identification of CYP7B1 as a novel target for PI3K/Akt and MAPK signalling. J Steroid Biochem Mol Biol. 2008;112(1–3):63–73.18790053
42. Tang W Eggertsen G Chiang JY Norlin M Estrogen-mediated regulation of CYP7B1: a possible role for controlling DHEA levels in human tissues J Steroid Biochem Mol Biol 2006 100 1–3 42 51 16720094
Tang W, Eggertsen G, Chiang JY, Norlin M. Estrogen-mediated regulation of CYP7B1: a possible role for controlling DHEA levels in human tissues. J Steroid Biochem Mol Biol. 2006;100(1–3):42–51.16720094
43. Olsson M Gustafsson O Skogastierna C Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma Prostate 2007 67 13 1439 46 17639508
Olsson M, Gustafsson O, Skogastierna C, et al. Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma. Prostate. 2007;67(13):1439–46.17639508
