Estrogen induces genomic instability in high-risk HPV-infected cervix and promotes the carcinogenesis of cervical adenocarcinoma

Ogawa, Minori; Hashimoto, Kae; Kitano, S; Yamashita, Saya; Toda, Aska; Nakamura, Koji; Kinose, Yasuto; Kodama, Michiko; Sawada, Kenjiro; Kimura, Tadashi

doi:10.1016/j.bbrc.2023.04.009

Cited by 12 publications

(8 citation statements)

References 18 publications

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“…For ovarian cancer, ESR1 expression has been found to be associated with the loss of chromosome 1p and 16q [ 39 ]. Estrogen signaling has also been found to induce genome instability in HPV-induced cervix and promote carcinogenesis in ovarian cancer [ 40 ]. Loss of ESR1 expression has been shown to enhance cervical cancer invasion [ 41 ] but how HPV (Human papillomavirus) might dysregulate the expression ER signaling genes will need further investigation [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

The prognostic value of MEK pathway–associated estrogen receptor signaling activity for female cancers

Ng,

Tsang,

Gershenson

et al. 2024

Br J Cancer

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Background Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness. Methods Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data. Results We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers. Conclusion This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.

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Section: Discussionmentioning

confidence: 99%

The prognostic value of MEK pathway–associated estrogen receptor signaling activity for female cancers

Ng,

Tsang,

Gershenson

et al. 2024

Br J Cancer

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“…Conversely, HPV infection, particularly high-risk HPV, is considered a risk factor for VGA development [ 7 ]. A recent study suggests a potential influence of estrogen on carcinogenesis in cervical adenocarcinoma cases with high-risk HPV infection [ 8 ]. However, the study acknowledges limitations in confirming whether estrogen itself triggers carcinogenesis, necessitating further research to validate this aspect.…”

Section: Discussionmentioning

confidence: 99%

Villoglandular Adenocarcinoma of the Uterine Cervix: A Case Report

Park,

Pak,

Park

2023

J Menopausal Med

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Cervical adenocarcinomas constitute for approximately 10%–20% of all invasive cervical cancers. Villoglandular adenocarcinomas (VGAs) are a rare subtype of cervical adenocarcinoma, representing approximately 5% of all cases of cervical adenocarcinomas. Herein, we report the case of a 49-year-old perimenopausal woman successfully treated for VGA. The patient presented to the hospital with a primary complaint of vaginal discharge persisting for 7 months with worsening symptoms. She had no underlying medical conditions or history of oral contraceptive use. A punch biopsy revealed an adenocarcinoma, and a human papillomavirus (HPV) test indicated positive for HPV-16. The patient underwent a radical hysterectomy with bilateral pelvic lymph node dissection, and a pathological diagnosis of VGA was established. After surgery, the patient underwent a 6-week course of concurrent chemoradiotherapy with cisplatin. During the 42 months of follow-up, no signs of disease recurrence or metastasis were observed. Because of the limitations of specimen acquisition, achieving a precise diagnosis through cervicovaginal cytology and punch biopsy is challenging. Instead, conization should be considered to prevent misdiagnosis.

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“…Specially, Díaz et al discovered that the expression of estrogen receptor-α (ERα) led to a strong upregulation of EAG1 expression in HeLa cells 76 , in response to both estradiol and anti-estrogen. Conversely, another study found that estradiol, through G protein-coupled receptor 30 (GPR30), rather than ERα, contributes to the destabilization of genome structure in HPV-infected cells, potentially promoting carcinogenesis 77 . This discrepancy may be due to different concentrations of estradiol, resulting in distinct mechanisms of action, which may be explained by the dual effects of estrogen concentrations.…”

Section: Mechanisms Underlying the Vd-vdr Signaling In Cervical Cancermentioning

confidence: 99%

Vitamin D and Its Receptors in Cervical Cancer

Dong,

Chen,

Liang

et al. 2024

J. Cancer

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Several studies have investigated the relationship between vitamin D (VD) and its receptors (VDR) and the risk of cervical cancer. However, the underlying mechanisms that underpin these associations remain incompletely comprehended. In this review, we analyzed the impacts of VD and VDR on cervical cancer and related mechanisms, and discussed the effects of VD, calcium, and other vitamins on cervical cancer. Our literature research found that VD, VDR and their related signaling pathways played indispensable roles in the occurrence and progression of cervical cancer. Epidemiological studies have established associations between VD, VDR, and cervical cancer susceptibility. Current studies have shown that the inhibitory effect of VD and VDR on cervical cancer may be attributed to a variety of molecules and pathways, such as the EAG potassium channel, HCCR-1, estrogen and its receptor, p53, pRb, TNF-α, the PI3K/Akt pathway, and the Wnt/β-catenin pathway. This review also briefly discussed the association between VDR gene polymorphisms and cervical cancer, albeit a comprehensive elucidation of this relationship remains an ongoing research endeavor. Additionally, the potential ramifications of VD, calcium, and other vitamins on cervical cancer has been elucidated, yet further exploration into the precise mechanistic underpinnings of these potential effects is warranted. Therefore, we suggest that further studies should focus on explorations into the intricate interplay among diverse molecular pathways and entities, elucidation of the mechanistic underpinnings of VDR polymorphic loci changes in the context of HPV infection and VD, inquiries into the mechanisms of VD in conjunction with calcium and other vitamins, as well as investigations of the efficacy of VD supplementation or VDR agonists as part of cervical cancer treatment strategies in the clinical trials.

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Estrogen induces genomic instability in high-risk HPV-infected cervix and promotes the carcinogenesis of cervical adenocarcinoma

Cited by 12 publications

References 18 publications

The prognostic value of MEK pathway–associated estrogen receptor signaling activity for female cancers

The prognostic value of MEK pathway–associated estrogen receptor signaling activity for female cancers

Villoglandular Adenocarcinoma of the Uterine Cervix: A Case Report

Vitamin D and Its Receptors in Cervical Cancer

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