Interaction of different steroid hormones during progression of tumour cells to steroid autonomy

Progression to steroid insensitivity poses a major problem in therapy of breast cancer, but studies of the origin of steroid-insensitive cells have been few and have concentrated in any one system on the loss of response to only one steroid. Since both normal and tumour mammary cells have complex endocrine requirements, we wondered how different steroids might interact during loss of steroid sensitivity. Cloned cells from the androgen-responsive Shionogi 115 mouse mammary carcinoma respond in vitro to both androgens and glucocorticoids in terms of both cellular and molecular parameters but, following prolonged absence of any steroid, these cells become unresponsive. We show here that 2 steroids can interact to prevent the progression to steroid insensitivity since the S115 cells can be protected against any loss of response to either androgen or glucocorticoid with either steroid alone. Androgen protects against loss of glucocorticoid sensitivity and glucocorticoid protects against loss of androgen sensitivity. The clinical implications are discussed.