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Tamoxifen Regulation of Ectocervical Cell Differentiation

Vineet Jain

Nywana Sizemore, PhD

George I. Gorodeski, MD, PhD

Richard L. Eckert, PhD

Departments of Environmental Health Sciences and Reproductive Medicine, Case Western Reserve University, Cleveland, Ohio

Ellen A. Rorke, PhD

Departments of Environmental Health Sciences and Reproductive Medicine, Case Western Reserve University, Cleveland, Ohio; Department of Environmental Science, School of Medicine, Case Western Reserve University, Cleveland, Ohio, 44106

Objective: To determine the effects of tamoxifen on the growth and differentiation of normal human cervical cells and compare those effects with those of a synthetic estrogen, diethylstilbestrol (DES). In addition, the effects of these compounds on immortalized cervical cells and cervical tumor cells were ascertained.

Methods: Growth curves were used to determine the effects on cell proliferation. The expression of several proteins was used to determine the effects on cell differentiation. Binding assays and Western analysis were used to determine estrogen receptor levels.

Results: Both tamoxifen and DES inhibited the proliferation of normal cervical cells. This growth inhibition was coincident with an increase in cell differentiation as determined by cornified envelope formation. The increase in envelope number was not accompanied by an increase in involucrin or cornifin, two protein precursors of the envelope. The activity of transglutaminase, which enzymatically incorporates precursor proteins into the envelope, was not stimulated following treatment. Diethylstilbestrol did not alter the growth or differentiation of the human papillomavirus 16-immortalized cell line ECE16-1 or any of the cervical tumor cell lines. Of all the immortalized or cancer cell lines, only Caski cells were growth inhibited by tamoxifen. Normal ectocervical epithelial cells and Caski cells expressed the high-affinity 56-kDa estrogen receptor, but ³H-estradiol binding was not detected in cell extracts from either ME180 or ECE16-1- cells. Nevertheless, extracts from ME180 cells contained on immunoreactive band at the appropriate molecular weight for the estrogen receptor.

Conclusions: These results suggest that tamoxifen and DES act similarly in normal cervical cells to promote cervical cell differentiation. However, because Caski cell growth was inhibited by tamoxifen and not DES, the effects of tamoxifen in thse cells may be mediated by non-estrogen receptor mechanisms.

Key Words: Ectocervix • tamoxifen • transglutaminase • cornified envelopes

Journal of the Society for Gynecologic Investigation, Vol. 2, No. 6, 754-761 (1995)
DOI: 10.1177/107155769500200606


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