Tamoxifen and proliferation of vaginal and cervical epithelium in postmenopausal women with breast cancer

Friedrich, Michael; Mink, D; Villena-Heinsen, C; Woll-Hermann, Astrid; Schmidt, Werner

doi:10.1016/s0301-2115(98)00117-1

Cited by 18 publications

(13 citation statements)

References 14 publications

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“…3). Many genes identified as estrogen-responsive in breast cancer studies followed the decrease in ERα expression but others showed increased expression levels, suggesting that estrogen may act through multiple direct and indirect pathways as well as major differences in estrogen effects on breast and reproductive tissues (64 (Table 3). Leading examples are cytokine ligands CXCL12 (65) whose increased expression recently was associated with HPV infection (66), CXCL14, and increased expression of interleukin 8 (IL-8) and decreased expression of its receptor CXCR2.…”

Section: Discussionmentioning

confidence: 99%

“…This further distinguishes cervical cancer from breast cancer, where ERβ is expressed and negatively modulates ERα's activity through heterodimerization (72). This could be at the basis of why many breast tumors respond favorably to estrogen receptor blockers such as tamoxifen, whereas adverse effects are observed in cervical and endometrial cancers (64). A proposed role for stromal expression of the endothelial protein TIE2 in estrogen-driven angiogenesis in breast cancers (73) is potentially consistent with our own immunofluorescence-based observation of TIE2 expression in cervical stroma, although we found that TIE2 expression is not restricted to ERα-positive stromal cells and is also moderately expressed in the epithelium.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Boon

Pyeon

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

213

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To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1-CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/ CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERα) to CxCa, ERα expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERα to FSP1+, CD34+, SMA− precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1−, CD34−, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERα mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERα-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERα+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERα in tumor-associated stromal fibroblasts.cervical cancer | HPV | estrogen | tumor microenvironment | stroma G lobally, cervical cancer (CxCa) is the second most common cancer in women, with >500,000 new cases each year, half of which are ultimately fatal (1). In the developed world, routine CxCa screening for abnormal cervical cytology, human papillomavirus (HPV), or both (2) has strongly reduced CxCa incidence, demonstrating the value of recognizing and removing early neoplasms (3). Such screening programs present a rare opportunity to study the sequential molecular changes in the development of a human cancer (4).CxCa development is related to infection with high-risk oncogenic HPVs, most prominently HPV16 and HPV18 (5-7). HPV oncoproteins E6 and E7 are best known for blocking tumor suppressor functions of p53 and Rb, respectively, but have numerous additional interaction partners (8-13). Most cervical HPV infections are cleared (14), but in a fraction of cases persistent infections lead to increasingly severe grades of dysplasia (cervical intraepithelial neoplasia grades 1, 2, and 3; CIN1, CIN2, CIN3) and ultimately to invasive cancer. Although the key steps of the carcinogenic process, HPV infection, progression to precancer, and invas...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Boon

Pyeon

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

226

213

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“…Based on this, several clinical trials have been carried out with tamoxifen that provided inconclusive results [52, 53]. Unfortunately tomoxifen was a poor choice of SERM to use as it acts as an ER agonist rather than ER antagonist in human cervix and vagina [54]. Tamoxifen has also been evaluated for its effect on proliferation of human cervical cancer cell lines; however, it is difficult to interpret these data because the cells used are apparently ERα-negative, and tamoxifen had differential effects depending on its concentration [28, 55, 56].…”

Section: Serms and Cervical Cancermentioning

confidence: 99%

Estrogen and ERα: Culprits in cervical cancer?

Chung¹,

Franceschi²,

Lambert³

2010

Trends in Endocrinology & Metabolism

170

154

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Estrogen and its receptors are implicated in the promotion and prevention of various cancers. While the uterine cervix is highly responsive to estrogen, the role of estrogen in cervical cancer, which is strongly associated with human papillomavirus (HPV) infections, is poorly understood. Recent studies in HPV transgenic mouse models provide evidence that estrogen and its nuclear receptor promote cervical cancer in combination with HPV oncogenes. While epidemiological studies further support this hypothesis, there is little experimental data assessing the hormonal responsiveness of human cervical cancers. If these cancers are dependent upon estrogen, then drugs targeting estrogen and its receptors may be effective in treating and/or preventing cervical cancer, the second leading cause of death by cancer amongst women worldwide.

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“…Another clinical study demonstrates that anti-estrogen tamoxifen has no beneficial effect on cervical cancer (17). This result is not surprising because tamoxifen has an agonistic rather than antagonistic effect on estrogen function in the human cervix (18). Thus there remains a poor understanding as to the estrogen-dependence of cervical cancers in humans.…”

Section: Introductionmentioning

confidence: 96%

Requirement for Estrogen Receptor α in a Mouse Model for Human Papillomavirus–Associated Cervical Cancer

et al. 2008

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The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPV), which encode the potent E6 and E7 oncogenes. On prolonged treatment with physiologic levels of exogenous estrogen, K14E7 transgenic mice expressing HPV-16 E7 oncoprotein in their squamous epithelia succumb to uterine cervical cancer. Furthermore, prolonged withdrawal of exogenous estrogen results in complete or partial regression of tumors in this mouse model. In the current study, we investigated whether estrogen receptor A (ERA) is required for the development of cervical cancer in K14E7 transgenic mice. We show that exogenous estrogen fails to promote either dysplasia or cervical cancer in K14E7/ERa À/À mice despite the continued presence of the presumed cervical cancer precursor cell type, reserve cells, and evidence for E7 expression therein. We also observed that cervical cancers in our mouse models are strictly associated with atypical squamous metaplasia (ASM), which is believed to be the precursor for cervical cancer in women. Consistently, E7 and exogenous estrogen failed to promote ASM in the absence of ERA. We conclude that ERA plays a crucial role at an early stage of cervical carcinogenesis in this mouse model.

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Tamoxifen and proliferation of vaginal and cervical epithelium in postmenopausal women with breast cancer

Cited by 18 publications

References 14 publications

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Estrogen and ERα: Culprits in cervical cancer?

Requirement for Estrogen Receptor α in a Mouse Model for Human Papillomavirus–Associated Cervical Cancer

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