Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis

Regions where one type of epithelium replaces another (metaplasia) have a p redilection for cancer formation. Environmental factors are closely linked to metaplastic carcinogenesis. In particular, cervical cancers associated w ith human papillomavirus (HPV) infection develop primarily at the transform ation zone, a region where metaplastic squamous cells are detected in other wise columnar epithelial-lined endocervical glands. Previously, we reported estrogen-induced multistage vaginal and cervical carcinogenesis in transge nic mice expressing HPV16 oncogenes in basal squamous epithelial cells. In the present study to investigate the threshold neoplastic response to exoge nous estrogen, we treated groups of transgenic mice with lower hormone dose s. A 5-fold reduction in estrogen dose induced squamous carcinogenesis sole ly at the cervical transformation zone compared with other reproductive tra ct sites. Further study delineated stages of transformation zone carcinogen esis, including formation of hyperplastic lower uterine glands and emergenc e of multiple foci of squamous metaplasia from individual stem-like glandul ar reserve cells, followed by neoplastic progression of metaplasia to dyspl asia and squamous cancer. We propose that a combination of low-dose estroge n and low-level HPV oncogene expression biases transformation zone glandula r reserve cells toward squamous rather than columnar epithelial fate decisi ons. Synergistic activation of proliferation by viral oncoprotein cell cycl e dysregulation and estrogen receptor signaling, together with altered para crine stromal-epithelial interactions, may conspire to support and promote neoplastic progression and cancer formation.