Loss of Estrogen Receptor 1 Enhances Cervical Cancer Invasion

Abstract

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 ...

Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina

“…Squamous cell carcinoma is the most common invasive malignancy of the cervix, vagina, and vulva (34). Although much remains to be learned about the underlying molecular mechanisms, loss of ESR1 has been associated with squamous cell carcinoma progression and invasion (35). Although we showed dysregulated epithelial cell proliferation and differentiation in the K5-Esr1KO mouse vagina and found that prolonged estrogen exposure induced abnormal epithelial invagination into the stroma, cancerous lesions and indications of metastatic phenotypes (e.g., effects on basement membrane) were not observed.…”

Decorin causes autophagy in endothelial cells via Peg3

“…Notably, these genes were induced exclusively in the tumor stroma of mouse origin but not in the mammary carcinomas of human origin (24). One of the most up-regulated genes was Paternally expressed gene 3 (Peg3), an imprinted putative tumor-suppressor gene frequently silenced by promoter hypermethylation and/or loss of heterozygosity (25)(26)(27)(28)(29)(30). Interestingly, Peg3 binds β-catenin and promotes 26S proteasomal degradation that is, surprisingly, independent of glycogen synthase kinase-3β GSK3β (31).…”

Genistein Increase Intracellular Distribution of the High Motility Group Box-1 through p38 Pathway in HeLa culture cells induced by Tumor Necrosis Factor-α

“…While in cervix cancer cells, estrogen receptor type that more dominant is estrogen receptor-α. Decreased levels of estrogen receptor-α in cervical cancer cells can increase malignancy of cancer cells [28,29,30]. Thus, it can be presumed that there are other pathways exist in addition to the estrogen receptor-α and -β that can increase the activation of p38 in our study.…”