Induction of Aromatase Expression in Cervical Carcinomas: Effects of Endogenous Estrogen on Cervical Cancer Cell Proliferation

Abstract

Epidemiologic studies have implicated estrogenic exposure as well as human papilloma virus (HPV) infection in cervical carcinogenesis, and some studies have suggested that estrogen and HPV may play synergistic roles in cervical tumorigenesis. In this study, we report a novel finding that f35% of cervical carcinomas tested (n = 19) express aromatase, the enzyme responsible for converting androgen to estrogen, the ratelimiting and final step in estrogen biosynthesis. On the other hand, no aromatase expression was detected in precancerous (n = 42) or normal cervical (n = 17) tissue samples. Increased aromatase was associated with increases in estrogen receptors (ER-A and ER-B) and a decrease in progesterone receptor levels, suggesting that in situ estrogen signaling via ER may be involved in tumor growth. Stable overexpression of aromatase in HPV + cervical cancer cells resulted in increased cellular proliferation, anchorage-independent growth, and ER expression and activity. In contrast, little change in ER was observed in HPV À cells. Steroid hormone receptor expression observed in vitro paralleled that seen in cervical carcinomas expressing aromatase. Aromatase overexpression also induced the expression of cyclin D1, proliferating cell nuclear antigen, and the HPV oncogenes, E6 and E7. Furthermore, the data underscores the importance of steroid receptor (estrogen and progesterone receptors) regulation in cervical carcinogenesis. To our knowledge, this is the first report demonstrating the induction of aromatase expression in cervical carcinomas, and opens the possibility that aromatase inhibitors may be potential therapeutic agents in cervical carcinomas expressing aromatase. (Cancer Res 2005; 65(23): 11164-73)

Inhibition of growth of cervical cancer cells using a dominant negative estrogen receptor gene

“…Recent reports suggested that the expression of cyclin D1, a major cell proliferation protein, is associated with estrogen-stimulation of growth in cervical tumors [22]. From our study (Figures 4a and b), there was a dramatic down-regulation of Cyclin D1 protein expression at 24, 48 and 72 hr after transfection with Ad-ER-DN but not after Ad-LacZ, indicating specific blockage of Cylcin D1 expression by Ad-ER-DN.…”

“…A novel observation recently provides strong evidence that increased estrogen signaling is essential to the growth of cervical tumor, i.e. increased expression of aromatase, estrogen receptors and cyclin D1 are significantly associated with growth of tumors [22]. Hence it is conceivable that blocking the estrogen pathway, specifically the activity of ER, might be a rational approach to reduce the expression of HPV E6 and E7, and alleviating the inhibition of p53 and pRb.…”

Gossypin as a Novel Selective Dual Inhibitor of v-raf Murine Sarcoma Viral Oncogene Homolog B1 and Cyclin-Dependent Kinase 4 for Melanoma

“…Each 25 mL reaction included 12.5 mL DyNamo master mix (Finnzymes) and 10 pmol of primers. The relative levels of p21, p27, cyclin D1, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcripts were calculated using the DC T method (31).…”

The Human Papilloma Virus – Ion Channel Link in Cancer: An Alternative Opportunity for Diagnosis and Therapy

“…In addition, overexpression of aromatase, the enzyme that transforms testosterone into estrogen, is known to increase estrogen activity in breast tissue, and in cervical cancers it has been reported that 35% of human cervical cancer tested express aromatase, but aromatase expression was not detected in precancerous or normal cervical tissue samples. Aromatase overexpression induced the expression of cyclin D1, proliferating cell nuclear antigen and HPV oncogenes (Nair, et al, 2005). It was also observed that women that expressed higher levels of estrogen receptors transcripts were significantly more likely to have cervical HPV infection; it may be that the presence of the receptor allows cellular acquisition of HPVand increased viral transcription (Shew, M., et al 2005).…”