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. 2013 Feb;4(1):50-9.
doi: 10.1007/s12672-012-0125-7. Epub 2012 Oct 13.

"V体育官网入口" Requirement for stromal estrogen receptor alpha in cervical neoplasia

Sang-Hyuk Chung  1 , Myeong Kyun Shin, Kenneth S Korach, Paul F Lambert
Affiliations

Requirement for stromal estrogen receptor alpha in cervical neoplasia

Sang-Hyuk Chung (VSports) et al. Horm Cancer. 2013 Feb.

Abstract

The major etiological factor for cervical cancer is the high-risk human papillomavirus (HPV), which encodes E6 and E7 oncogenes. However, HPV is not sufficient, and estrogen has been proposed as an etiological cofactor for the disease VSports手机版. Its requirement has been demonstrated in mouse models for HPV-associated cervical cancer (e. g. , K14E7 transgenic mice). Although germline knockout of estrogen receptor alpha (ERα) renders mice resistant to cervical cancer, the cell-type-specific requirement for ERα is not known. In this study, we demonstrate that temporal deletion of stromal ERα induced complete regression of cervical dysplasia in K14E7 mice. Our results strongly support the hypothesis that stromal ERα is necessary for HPV-induced cervical carcinogenesis and implicate paracrine mechanisms involving ERα signaling in the development of estrogen-dependent cervical cancers. This is the first evidence to support the importance of stromal ERα in estrogen-dependent neoplastic disease of the female reproductive tract. .

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Tamoxifen induces efficient deletion of ERα only in cervical stroma of CMVCreER/ERα f/f mice. a Tamoxifen treatment induces atrophic female reproductive tracts in CMVCreER/ERα f/f mice. ERα f/f (CMVCreER−, left) and CMVCreER/ERα f/f (CMVCreER+, right) mice were i.p. injected with tamoxifen (4 mg/day for 5 days). The female reproductive tracts were harvested 2 weeks after the first dose. Black and red arrowheads indicate ovaries and hemorrhagic cysts, respectively. u uterus, c cervix, v vagina. Scale bar, 5 mm. b ERα expression is retained in the cervical epithelium of CMVCreER/ERα f/f mice treated with tamoxifen. Mice were treated as in a and paraffin sections were stained for ERα (green). DAPI-stained nuclei are pseudocolored red. Note that ERα is readily detected in cervical epithelium (e) but not in cervical stroma (s) (upper panel) and both compartments of the uterus (bottom panel) in CMVCreER/ERα f/f mice. Dotted lines indicate basement membrane separating epithelium from stroma. Scale bar, 50 μm
Fig. 2
Fig. 2
Cervical disease is absent in CMVCreER/K14E7/ERα f/f mice treated with tamoxifen. a Treatment regimen is depicted. E2 and Tam indicate estrogen and tamoxifen, respectively. b Shown are high-magnification images of representative H&E-stained endocervical sections from indicated groups of mice. Arrows point to atypia manifested as dark and enlarged nuclei. Note that cervical intraepithelial neoplasia (CIN) is evident in K14E7/ERα f/f 8mE2 (−Tam), CMVCreER/K14E7/ERα f/f 8mE2 (−Tam), and K14E7/ERα f/f 8mE2 (+Tam) mice (panels i–iii) but absent in CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice (panel iv). Scale bar, 20 μm
Fig. 3
Fig. 3
Cervical disease states correlates with the ERα status in the cervical stroma. a ERα expression is ablated in the cervical stroma of CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice without cervical disease. Paraffin sections of female reproductive tracts from indicated groups of mice were stained for ERα (green). All diseased mice expressed ERα in both epithelium and stroma of the cervix (panels i–iii), yet ERα was barely detectable in the cervical stroma of disease-free CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice (panel iv). DAPI-stained nuclei are pseudocolored red. Scale bar, 20 μm. b Results shown in a and c were quantified for number of ERα+ cells. At least 1,000 cervical stromal cells in four random fields of each female reproductive tract were analyzed. Data are shown as mean ± SEM. p value for two-sided Wilcoxon rank sum test is shown. c ERα expression is retained in cervical stroma of CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice with CIN. Paraffin sections from female reproductive tracts of the two mice that had cervical disease in the CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) group were stained for ERα (green). DAPI-stained nuclei are pseudocolored red. Scale bar, 20 μm. d Epithelial ERα is not deleted shortly after tamoxifen treatment. Mice were treated with E2 for 6 months, treated with tamoxifen (4 mg) for 3 days (top panel) or 5 days (bottom panel), and killed a day later. Paraffin sections were subjected to ERα IHC (green). DAPI-stained nuclei are pseudocolored red. Scale bar, 50 μm. e PR is expressed in the cervical epithelium of CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice. Cervical tissues from indicated study groups were subjected to PR IHC (brown nuclei). Nuclei were counterstained with hematoxylin. Representative images from three mice in each group are shown. The black lines point to basement membrane. Scale bar, 50 μm
Fig. 4
Fig. 4
Cervical epithelial cell proliferation is significantly reduced when ERα expression is ablated in the stromal cells. a BrdU incorporation is reduced in the cervical epithelia of CMVCreER/K14E7/ERα f/f 8mE2 (+Tam) mice. Paraffin sections from indicated study groups were stained for BrdU to measure cell proliferation (brown nuclei). Nuclei were counterstained with hematoxylin. Representative images from three mice for each group are shown. Scale bar, 20 μm. b BrdU+ cells shown in a were quantified. Data are shown as mean ± SEM (n = 3). p values for two-sided Wilcoxon rank sum test are shown
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