The probability that a mouse develops a pulmonary
tumor, as well as the structure of that
tumor, are dependent on several genes. Three pulmonary
adenoma susceptibility (pas) genes predispose some inbred strains to develop lung
tumors, even in the absence of
carcinogen exposure, and cause others to be resistant. One pas gene is K-ras, which may also be overexpressed in these
tumors in a mutated form capable of transforming cells. Mice with activated Ha-ras transgenes override the resistant pas alleles and are born with
lung cancer. Susceptible strains have a higher turnover rate of alveolar type II and bronchiolar Clara cells, those cells from which lung
tumors arise, than more resistant strains. A high precursor cell turnover rate correlates with a propensity to
neoplasia in other animal models as well, possibly due to low concentrations of endogenous growth regulatory molecules such as
corticosterone and
protein kinase C (PKC). Neoplastic lung epithelial cells are relatively resistant to
glucocorticoids and have low PKC levels. A set of genes other than the pas genes governs the response to
tumor modulation by
butylated hydroxytoluene (
BHT). The genes that determine whether lung
tumor multiplicity is enhanced by chronic
BHT exposure may regulate the ability to hydroxylate
BHT at a tert-butyl position to form
BHT-OH, a metabolite with greater
tumor-promoting potency than
BHT. Inbred and recombinant inbred strain variations in
adenoma growth patterns indicate that another set of genes, which we have designated pah for pulmonary
adenoma histogenesis, may determine which cell type becomes neoplastic and whether
adenomas will undergo malignant conversion.