Induction of aromatase expression in cervical carcinomas: effects of endogenous estrogen on cervical cancer cell proliferation.
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 approximately 35% of cervical carcinomas tested (n = 19) express aromatase, the enzyme responsible for converting androgen to estrogen, the rate-limiting 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-alpha and ER-beta) 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- 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.
Nair
Hareesh B
HB
Department of Gynecology and Obstetrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Luthra
Roopa
R
Kirma
Nameer
N
Liu
Ya-Guang
YG
Flowers
Lisa
L
Evans
Dean
D
Tekmal
Rajeshwar Rao
RR
D001141:Aromatase / Q000096:biosynthesis* / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000201:enzymology; D019938:Cyclin D1 / Q000378:metabolism; D004790:Enzyme Induction; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D027383:Papillomaviridae; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D030361:Papillomavirus Infections / Q000201:enzymology / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000821:virology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D050725:Papillomavirus E7 Proteins; D018809:Proliferating Cell Nuclear Antigen; D011980:Receptors, Progesterone; D019938:Cyclin D1; D001141:Aromatase