Estrogen receptor localization in normal and neoplastic epithelium of the uterine cervix

Nonogaki, Hirofumi; Fujii, Shingo; Konishi, Ikuo; Nanbu, Yoshihiko; Ozaki, Shunsuke; Ishikawa, Yuichi; Mori, Takahide

doi:10.1002/1097-0142(19901215)66:12<2620::aid-cncr2820661226>3.0.co;2-s

Cited by 38 publications

(33 citation statements)

References 23 publications

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“…As noted in previous studies, ESR1 expression in normal epithelium was primarily observed in the basal portions of the epithelium. 15 To determine whether HPV presence or particular type correlated with ESR1 expression, the HPV status of each tissue sample was determined using PCR amplification of DNA samples using one or more sets of consensus primers, followed by direct sequencing of the PCR products. We identified no correlation between HPV status or HPV type with loss of ESR1 expression (Supplemental Table S2 at http//ajp.amjpathol.org).…”

Section: Expression Of Esr1 Is Low In Most Invasive Cervical Carcinommentioning

confidence: 99%

Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion

Zhai

Bommer

Feng

et al. 2010

The American Journal of Pathology

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If left untreated, some cervical high-grade squamous intraepithelial lesions will progress to invasive squamous cell carcinoma (SCC), but the molecular events conferring invasive potential remain poorly defined. In prior work, we identified 48 genes that were downregulated in SCCs compared with high-grade squamous intraepithelial lesions and normal squamous epithelia. In this study, a functional screening strategy was used to identify which of these genes regulate cervical cancer cell invasion. Two independent squamous epithelial cell lines were transduced with a library of short hairpin RNAs targeting the differentially expressed genes and tested for invasion of the chick chorioallantoic membrane. PCR was used to recover specific short hairpin RNAs from cells that invaded the chorioallantoic membrane. Constructs targeting estrogen receptor 1 (ESR1) were highly enriched in the invasive cells. The short hairpin RNAmediated inhibition of ESR1 in SCC-and precancerderived cell lines increased invasiveness in both in vivo and in vitro assays. Conversely, restoration of ESR1 expression in ESR1-negative cervical cancer cells reduced cell invasiveness. Loss of ESR1 expression was found to accompany cervical cancer progression in an analysis of primary normal cervix, low grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, and SCC specimens. Molecular mechanisms underlying down-regulation of ESR1 in invasive cervical carcinomas appear to be complex and likely heterogeneous. Our findings indicate that loss of ESR1 has a major role in mediating cervical cancer invasion and progression. Cervical cancer is the second most prevalent cancer in women worldwide, accounting for nearly a half million new cases and 274,000 deaths each year.1 Although cervical cytology screening has greatly reduced cervical cancer incidence and mortality in developed countries, cervical cancer remains a major cause of cancer-related mortality in developing countries, particularly in sub-Saharan Africa, Latin America, the Caribbean, and portions of south Asia. Even in developed countries, the cost and morbidity associated with management of cervical cancer precursor lesions, referred to as low-grade and highgrade squamous intraepithelial lesions (LSILs and HSILs, respectively) remain substantial. If left untreated, upwards of 10 to 15% of high-grade pre-invasive lesions will progress to invasive squamous cell carcinoma (SCC), while nearly a third will regress.2,3 However, because morphological assessment alone does not allow distinction of those HSILs likely to progress from those that will regress spontaneously, surgical excision of HSILs remains the clinical standard of care. 4 In light of these considerations, there is substantial interest in identifying molecular mediators of progression from noninvasive cervical cancer precursor lesions to invasive carcinoma. Some factors might also prove to be useful biomarkers of progression risk.To identify genes whose differential expression is linked to progression from HSIL ...

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Section: Expression Of Esr1 Is Low In Most Invasive Cervical Carcinommentioning

confidence: 99%

Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion

Zhai

Bommer

Feng

et al. 2010

The American Journal of Pathology

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“…Like the breast, the uterine cervix is a target tissue for steroid hormones and contains oestrogen receptors in endocervical epithelium, stromal cells and basal layers of squamous epithelium (Kupryjanczyk & Moller, 1988;Cano et al, 1990;Nonogaki et al, 1990). In this preliminary study we have shown, as far as we are aware for the first time, that a proportion of cervical adenocarcinomas also contain immunocytochemically detectable ER protein; this finding was associated with a good prognosis.…”

Section: Discussionmentioning

confidence: 58%

“…Previous studies using the dextran coated charcoal method (Martin et al, 1978;Ford et al, 1983;Gao et al, 1983; (Nonogaki et at., 1990) none of the six cervical adenocarcinomas examined showed ER immunoreactivity.…”

Section: Discussionmentioning

confidence: 99%

“…This is shown by menstrual cycle related alterations in the quality of cervical mucus (Wakefield & Wells, 1985), and the demonstration of oestrogen and progesterone receptors in the normal cervix (Kupryjanczyk & M6ller, 1988;Cano et al, 1990;Nonogaki et al, 1990). While the clinical and biological significance of oestrogen receptor status in breast carcinoma has been extensively studied, very little factual information is available on the presence of oestrogen receptors in cervical adenocarcinoma.…”

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confidence: 99%

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Oestrogen receptor protein and mRNA in adenocarcinoma of the uterine cervix

Ismail

Thomas²,

Ghandour³

et al. 1992

Br J Cancer

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Summary We have investigated the oestrogen receptor (ER) status of 20 cervical adenocarcinomas by immunocytochemistry for ER protein and non-isotopic in situ hybridisation for ER mRNA. Both methods, which are applicable to paraffin sections, were developed and validated in breast carcinomas with known ER content. Six cervical adenocarcinomas contained immunocytochemically demonstrable ER protein; all contained ER mRNA, but staining was less intense in poorly differentiated areas of four tumours. This disparity between protein and mRNA detection needs further investigation as does the possibility that oestrogens may play a role in the pathogenesis of cervical adenocarcinoma.Adenocarcinoma of the cervix is a relatively rare tumour which is increasing in incidence among young women (Peters et al., 1986;Schwartz & Weiss, 1986;Chilvers et al., 1987). Little is known of its aetiology and pathogenesis.The cervix, like the breast, is a target tissue for oestrogens and progesterone. This is shown by menstrual cycle related alterations in the quality of cervical mucus (Wakefield & Wells, 1985), and the demonstration of oestrogen and progesterone receptors in the normal cervix (Kupryjanczyk & M6ller, 1988;Cano et al., 1990;Nonogaki et al., 1990). While the clinical and biological significance of oestrogen receptor status in breast carcinoma has been extensively studied, very little factual information is available on the presence of oestrogen receptors in cervical adenocarcinoma.Having validated our methodology in a series of breast carcinomas with known ER protein content, we studied ER mRNA and protein content of 20 cervical adenocarcinomas. Materials and methods ImmunocytochemistryAll tissues were fixed in 10% formol saline and embedded in paraffin wax. Five ym sections were dewaxed, rehydrated and immunostained using a modification of an avidinbiotin-peroxidase complex technique for detection of ER (Andersen et al., 1986;Cheng et al., 1988). After blocking endogenous peroxidase activity the sections were digested at 37°C in a 0.02% Pronase E (Sigma, P6911) solution for 20-30min. The washed slides were incubated with normal swine serum, followed by application of anti-ER monoclonal antibody (H222) or control antibody (rat IgG) overnight at room temperature. After washing, the slides were incubated at room temperature with biotinylated sheep anti-rat IgG (Amersham) for 30 min, and avidin-biotin complex (Dako) for 1 h. The reaction was developed with diaminobenzidine. The staining was intensified by immersing the slides for 10 min in 0.5% CuSO4 in 0.85% NaCl. Counterstaining was performed with 1% methylgreen.In situ hybridisation A 24 base cDNA oligonucleotide probe (5' CTC CAG CTC GTT CCC TTG GAT CTG 3') complementary to human ER mRNA coding for amino acids 17-24 was synthesised to our specifications (British Bio-technology Ltd., Abingdon, (Green et al., 1986;Pelletier et al., 1988;Ponglikitmongkol et al., 1988;Graham et al., 1991). The probe was labelled at the 5' end with digoxigenin-l 1-UTP and purified by HPLC. A 2...

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“…[24][25][26][27] Despite some opposite results, it broadly appears that the expression of E 2 -R and P 4 -R is higher in SIL biopsies compared with normal ectocervix and Published in: American Journal of Obstetrics and Gynecology (2003), vol. 189, iss.…”

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confidence: 99%

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix

Remoué

Jacobs

Miot

et al. 2003

American Journal of Obstetrics and Gynecology

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OBJECTIVE: Because sex hormones may be involved in tumor initiation and progression, we analyzed the presence of hormone receptors in the transformation zone of the uterine cervix where the majority of human papillomavirus infections and associated (pre)neoplastic lesions develop. STUDY DESIGN: By using 23 total hysterectomy samples from young women who underwent surgery for noncervical benign uterine disease, we analyzed, by immunohistologic techniques, the in situ expression of estrogen (E 2 -R) and progesterone (P 4 -R) receptors in the transformation zone and ectocervix of the same women. RESULTS: The expression of estrogen receptors and progesterone receptors is significantly higher in the transformation zone compared with the ectocervix. Immunohistochemical localization indicated that hormone receptor-positive cells are mainly observed in (para)basal and intermediate cell layers in both the transformation zone and ectocervical epithelium. When transformation zone samples were segregated into epithelial tissues with a predominantly mature (7/23 samples) or immature (16/23 samples) squamous metaplasia, only biopsy specimens with immature squamous metaplasia showed a significantly higher density of hormone receptorpositive cells compared with ectocervical epithelium (P < .01). CONCLUSION: Our results suggest that the cervical transformation zone may be at increased risk of the development of cancer because of a high sensitivity to sex hormone regulation. Key words: Transformation zone, hormone receptor, uterine cervix, cancerA substantial majority of cancers and precursor lesions (squamous intraepithelial lesions; SILs) develop within a specific region of the cervix, the transformation zone (TZ), 1 where the glandular epithelium of the endocervix is transformed progressively into a squamous epithelium during a process called metaplasia, which can be considered as a stepwise progression of changes. In the first phase, endocervical "reserve" cells proliferate and stratify.2 After, these cells differentiate into squamous cells that initially have only a slightly increased amount of cytoplasm and which undermine the endocervical epithelium that is often seen as a residual layer on the surface (immature squamous metaplasia). Later, the cells may mature fully to squamous cells that are indistinguishable from the superficial cells of the ectocervix. 3The chronic infection of metaplastic keratinocytes of the TZ by oncogenic types of human papillomavirus (HPV) is associated with the induction of SIL, which may result in the development of cervical invasive cancer. 4 Despite the evidence that HPV is implicated strongly as the causative agent of cervical cancer, HPV infection alone is not sufficient for SIL development. In addition to immune, microbial, or chemical cofactors, 5-7 sex hormones may play a role in the development of SIL. Indeed, the variation of hormonal status that depends on age, pregnancy, or contraceptive use, has been shown to influence the development of cervical (pre)neoplastic lesions. [8][...

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Estrogen receptor localization in normal and neoplastic epithelium of the uterine cervix

Cited by 38 publications

References 23 publications

Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion

Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion

Oestrogen receptor protein and mRNA in adenocarcinoma of the uterine cervix

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix

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