Resistance of Human Squamous Carcinoma Cells to Transforming Growth Factor β1 is a Recessive Trait

Because most human squamous carcinoma cell lines of the aerodigestive and genital tracts are refractory to the antiproliferative action of transforming growth factor β 1 (TGFβ 1) in vitro, we have begun to identify the causes for resistance of squamous carcinoma cell lines to TGFβ 1 by using somatic cell genetics. Two stable hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) were obtained by fusing a TGFβ 1-resistant human squamous carcinoma cell line, FaDu-HygR, with a human papilloma virus 16-immortalized, TGFβ 1-sensitive, human foreskin keratinocyte cell line, HKc-neoR. Whereas TGFβ 1 did not inhibit DNA synthesis in parental FaDu-HygRcells, it reduced DNA synthetic activity of HKc-neoR, FaDu-HKc.1, and FaDu-HKc.2 cells by 75-85% (IC50, 2-5 pM). Although squamous carcinoma cells express lower than normal levels of TGFβ 1 type II receptors on their cell surface, TGFβ 1 type II receptor mRNA was detected in all four cell lines. Recessive genes involved in TGFβ 1 signaling may be localized to the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in parental FaDu-HygRcells. Furthermore, our previous observation that mutant p53 decreases sensitivity of keratinocytes to TGFβ 1 was supported by the finding that the level of the mutant p53 protein expressed by the hybrid cell lines was greatly reduced. In summary, TGFβ 1 resistance of FaDu cells appears to be recessive and is presumably due to the loss of one or more post-receptor elements of the signaling pathway.