Induction of skin papillomas, carcinomas, and sarcomas in mice in which the connexin 43 gene is heterologously deleted

It has been suggested that blocked gap junctional intercellular communicati on plays a crucial part in multistage carcinogenesis. The mouse skin tumor- promoting phorbol esters are potent inhibitors of gap junctional intercellu lar communication and this inhibition is considered to be a mechanism by wh ich clonal expansion of "initiated" cells is promoted. We examined whether mice in which the gene for a gap junction protein, connexin 43, is heterozy gously deleted are more susceptible to chemical carcinogenesis; connexin 43 is expressed in the basal cell layer and the dermis of the skin. When the back skin was painted with 7,12-dimethylbenz[a]anthracene and 12-O-tetradec anoylphorbol 13-acetate, the incidence and yields of both papillomas and ca rcinomas were similar in connexin 43(+/-) and connexin 43(+/+) mice; for th is experiment, the original mice with C57BL/6 genetic background was crosse d with CD1 strain for three generations. Subcutaneous injection of 7,12-dim ethylbenz[a]anthracene resulted in induction of fibrosarcomas in connexin 4 3(+/-) and connexin 43(+/+) mice to a similar extent. All papillomas and ca rcinomas induced with 7, 12-dimethylbenz[a] anthracene and 12-O-tetradecano ylphorbol 13-acetate contained the 7,12-dimethylbenz[a]anthracene-specific mutation in the vas gene (A to T transversion at the 61st codon), About 50% of fibrosarcomas also contained this mutation, but in the Ki-ras gene; the re was no difference in the prevalence of this mutation in tumors from conn exin 43(+/-) and connexin 43(+/+) mice. None of the tumors examined, howeve r, showed any mutation in the connexin 43 gene. These results suggest that the deletion of one allele of the connexin 43 gene does not significantly c ontribute to, nor alter, the molecular events involved in skin carcinogenes is, These results are compatible with previous observations that nongenetic disruption of function rather than mutations of connexins, commonly occurs in cancer cells.