Variability of Androgen-related Phenotypes in the Shionogi Mammary Carcinoma during Growth, Involution, Recurrence, and Progression to Hormonal Independence1

Several parameters of androgen action were measured in hormone-dependent Shionogi carcinoma cells during phases of growth, regression, and recurrence. In the parental C1 line under steady state conditions, dihydrotestosterone is localized exclu sively in the nucleus while testosterone is confined almost entirely to the cytoplasm. After castration, the concentration of testos terone declines more rapidly than that of dihydrotestosterone. Spontaneous recurrent growth is not accompanied by significant elevation of the whole-tissue concentration of either androgen. Neither are changes observed in the concentration of cytoplasmic receptor or in the rate of uptake of androgens into the nucleus. However, relapse is associated with the appearance of a glucose-6-phosphate dehydrogenase double-enzyme phenotype and a loss of responsiveness to androgen withdrawal. The autonomous C3 variant line which is devoid of androgen-related markers is characterized by a deficiency of androgen retention by whole tissue and possibly a permeability defect of the plasma membrane. This variant tends to express a glucose-6-phosphate dehydrogenase double-enzyme phenotype. In contrast, the au tonomous C4 variant line retains the ability to concentrate mod est levels of testosterone in whole tissue and high levels of dihydrotestosterone in the nucleus. Although the number of nuclear binding sites is the same as that observed in the parental C1 line, the concentration of cytoplasmic receptor and the rate of nuclear uptake of androgens are relatively decreased. Expres sion of a glucose-6-phosphate dehydrogenase double-enzyme phenotype is less frequent than in the autonomous C3 variant line. The above results suggest that a recurrent tumor may contain hormone-sensitive cells which resume growth in an androgen-depleted environment. They also imply that progres sion from the androgen-dependent to the autonomous condition involves the selection and outgrowth of hormone-insensitive cells of variable phenotype.