“…Several previous studies have reported an interesting phenomenon in which there was low or no expression of ERα and PR in tumor cells of cervical cancer, despite an obvious expression in cervical stromal cells. 16 , 17 Furthermore, ERα and PR have been associated with survival in patients with cervical cancer. 16 In the current study, the expression of ERα and PR in tumor cells was used as an assessment criterion to make the model more practical, as cervical biopsy tissue includes tumor cells, but may not include normal stroma.…”
Section: Discussionmentioning
confidence: 99%
“…Stratified comparison was performed by defining the following two categories: negative expression (IRS 0) and positive expression (IRS ≥1) ( Figure 1 ). 14 , 16 Figure 1 Immunohistochemical staining of ER and PR expressions. ( 1Ai, 1Aii ) (cervical squamous cell carcinoma with stage IB1) and ( 1Bi, 1Bii ) (cervical squamous cell carcinoma with stage IB1) show the positive and negative ERα expression, respectively; ( 1Ci, 1Cii) (cervical adenocarcinoma with stage IB1) and ( 1Di, 1Dii) (cervical squamous cell carcinoma with stage IB1) show the positive and negative PR expression, respectively.…”
Objective
This study aimed to identify a subset of patients with stage IA2 to IIA2 cervical cancer who are at low risk of lymph node metastasis (LNM) using pathological parameters including estrogen receptor alpha (ERα) and progesterone receptor (PR).
Methods
The clinical data of patients with stage IA2 to IIA2 cervical cancer who underwent radical surgery between 2014 and 2015 were retrospectively reviewed. Immunohistochemical staining was used to determine the expression of ERα and PR. A low-risk criterion for LNM was identified using logistic regression analysis, and its performance was estimated through receiver-operating characteristic curve analysis.
Results
Of 263 patients, 57 (21.7%) had pathological LNM. ERα (adjusted odds ratio [aOR], 7.582; 95% confidence interval [CI], 2.991–19.222; P < 0.001) and squamous cell carcinoma (aOR, 3.520; 95% CI, 1.887–6.568; P < 0.001) were identified as independent predictors for no LNM by multivariate logistic regression analysis, while PR had no effect on LNM. The rate of LNM was 1.4% for low-risk patients (n = 73) identified as ERα positive with squamous cell carcinoma. The 5-year disease-free survival in low-risk patients was significantly greater than in those negative for ERα and/or those with non-squamous cell carcinoma (96.9% vs 80.1%, P = 0.002).
Conclusion
ERα positivity and squamous cell carcinoma are associated with a low risk of LNM in patients with stage IA2 to IIA2 cervical cancer. Hence, those patients without a low risk of LNM could be considered for definitive chemoradiotherapy to avoid unnecessary surgery.
“…Several previous studies have reported an interesting phenomenon in which there was low or no expression of ERα and PR in tumor cells of cervical cancer, despite an obvious expression in cervical stromal cells. 16 , 17 Furthermore, ERα and PR have been associated with survival in patients with cervical cancer. 16 In the current study, the expression of ERα and PR in tumor cells was used as an assessment criterion to make the model more practical, as cervical biopsy tissue includes tumor cells, but may not include normal stroma.…”
Section: Discussionmentioning
confidence: 99%
“…Stratified comparison was performed by defining the following two categories: negative expression (IRS 0) and positive expression (IRS ≥1) ( Figure 1 ). 14 , 16 Figure 1 Immunohistochemical staining of ER and PR expressions. ( 1Ai, 1Aii ) (cervical squamous cell carcinoma with stage IB1) and ( 1Bi, 1Bii ) (cervical squamous cell carcinoma with stage IB1) show the positive and negative ERα expression, respectively; ( 1Ci, 1Cii) (cervical adenocarcinoma with stage IB1) and ( 1Di, 1Dii) (cervical squamous cell carcinoma with stage IB1) show the positive and negative PR expression, respectively.…”
Objective
This study aimed to identify a subset of patients with stage IA2 to IIA2 cervical cancer who are at low risk of lymph node metastasis (LNM) using pathological parameters including estrogen receptor alpha (ERα) and progesterone receptor (PR).
Methods
The clinical data of patients with stage IA2 to IIA2 cervical cancer who underwent radical surgery between 2014 and 2015 were retrospectively reviewed. Immunohistochemical staining was used to determine the expression of ERα and PR. A low-risk criterion for LNM was identified using logistic regression analysis, and its performance was estimated through receiver-operating characteristic curve analysis.
Results
Of 263 patients, 57 (21.7%) had pathological LNM. ERα (adjusted odds ratio [aOR], 7.582; 95% confidence interval [CI], 2.991–19.222; P < 0.001) and squamous cell carcinoma (aOR, 3.520; 95% CI, 1.887–6.568; P < 0.001) were identified as independent predictors for no LNM by multivariate logistic regression analysis, while PR had no effect on LNM. The rate of LNM was 1.4% for low-risk patients (n = 73) identified as ERα positive with squamous cell carcinoma. The 5-year disease-free survival in low-risk patients was significantly greater than in those negative for ERα and/or those with non-squamous cell carcinoma (96.9% vs 80.1%, P = 0.002).
Conclusion
ERα positivity and squamous cell carcinoma are associated with a low risk of LNM in patients with stage IA2 to IIA2 cervical cancer. Hence, those patients without a low risk of LNM could be considered for definitive chemoradiotherapy to avoid unnecessary surgery.
“…However, cervical cancer-derived cell lines and later stage cervical cancer show low-level expression of ESR1 [ 20 , 21 ]. Furthermore, ESR1 is unnecessary in the process of the progression from high-grade squamous intraepithelial lesions (HSIL)/CIN3 to squamous cell carcinoma (SCC) [ 20 – 23 ]. Therefore, the role of ESR1 in the development of CIN and the significance of ESR1 reduction in CIN3 and SCC are not sufficiently clear.…”
Since cervical cancer still afflicts women around the world, it is necessary to understand the underlying mechanism of cervical cancer development. Infection with HPV is essential for the development of cervical intraepithelial neoplasia (CIN). In addition, estrogen receptor signaling is implicated in the development of cervical cancer. Previously, we have isolated human wings apart-like (WAPL), which is expected to cause chromosomal instability in the process of HPV-infected precancerous lesions to cervical cancer. However, the role of WAPL in the development of CIN is still unknown. In this study, in order to elucidate the role of WAPL in the early lesion, we established WAPL overexpressing mice (WAPL Tg mice) and HPV E6/E7 knock-in (KI) mice. WAPL Tg mice developed CIN lesion without HPV E6/E7. Interestingly, in WAPL Tg mice estrogen receptor 1 (ESR1) showed reduction as compared with the wild type, but cell growth factors MYC and Cyclin D1 controlled by ESR1 expressed at high levels. These results suggested that WAPL facilitates sensitivity of ESR1 mediated by some kind of molecule, and as a result, affects the expression of MYC and Cyclin D1 in cervical cancer cells. To detect such molecules, we performed microarray analysis of the uterine cervix in WAPL Tg mice, and focused MACROD1, a co-activator of ESR1. MACROD1 expression was increased in WAPL Tg mice compared with the wild type. In addition, knockdown of WAPL induced the downregulation of MACROD1, MYC, and Cyclin D1 but not ESR1 expression. Furthermore, ESR1 sensitivity assay showed lower activity in WAPL or MACROD1 downregulated cells than control cells. These data suggested that WAPL increases ESR1 sensitivity by activating MACROD1, and induces the expression of MYC and Cyclin D1. Therefore, we concluded that WAPL not only induces chromosomal instability in cervical cancer tumorigenesis, but also plays a key role in activating estrogen receptor signaling in early tumorigenesis.
“…In addition to AR, steroid hormone NRs in CAFs, including ERα and β, PR and GR, are also relatively well-studied. The expression of ERα has been detected in the CAFs of breast [ 13 ], endometrial [ 32 ], cervical [ 33 ] and prostate cancers [ 34 ], but not in colorectal carcinoma [ 35 ]. However, the clinical implications of ERα are diverse.…”
Section: Introductionmentioning
confidence: 99%
“…In some studies, ERα-expressing CAFs have been reported to promote prostate and endometrial cancer cell proliferation [ 32 , 36 ]; in other studies, CAFs attenuated prostate tumor cell invasiveness and immune cell infiltration by altering the levels of anti-angiogenic factors, ECM remodeling factors as well as chemokines, in addition to conserving chemosensitivity in certain breast cancer cell lines [ 37 – 39 ]. Similarly, divergent results have also been obtained in clinical biopsies, in which one association study found a positive correlation between ERα expression in CAFs with advanced prostate cancer stage [ 34 ], while the reverse trend was found in cervical cancer [ 33 ]. Despite these perplexing findings, a recent comparative transcriptomic study demonstrated differential expression patterns between CAFs isolated from early- and late-stage cervical cancer, with the latter being more metabolically and proliferatively active upon estradiol exposure [ 40 ].…”
The tumor microenvironment is a complex and dynamic cellular community comprising the tumor epithelium and various tumor-supporting cells such as immune cells, fibroblasts, immunosuppressive cells, adipose cells, endothelial cells, and pericytes. The interplay between the tumor microenvironment and tumor cells represents a key contributor to immune evasiveness, physiological hardiness and the local and systemic invasiveness of malignant cells. Nuclear receptors are master regulators of physiological processes and are known to play pro−/anti-oncogenic activities in tumor cells. However, the actions of nuclear receptors in tumor-supporting cells have not been widely studied. Given the excellent druggability and extensive regulatory effects of nuclear receptors, understanding their biological functionality in the tumor microenvironment is of utmost importance. Therefore, the present review aims to summarize recent evidence about the roles of nuclear receptors in tumor-supporting cells and their implications for malignant processes such as tumor proliferation, evasion of immune surveillance, angiogenesis, chemotherapeutic resistance, and metastasis. Based on findings derived mostly from cell culture studies and a few in vivo animal cancer models, the functions of VDR, PPARs, AR, ER and GR in tumor-supporting cells are relatively well-characterized. Evidence for other receptors, such as RARβ, RORγ, and FXR, is limited yet promising. Hence, the nuclear receptor signature in the tumor microenvironment may harbor prognostic value. The clinical prospects of a tumor microenvironment-oriented cancer therapy exploiting the nuclear receptors in different tumor-supporting cells are also encouraging. The major challenge, however, lies in the ability to develop a highly specific drug delivery system to facilitate precision medicine in cancer therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
