A major problem in treatment of cancers arising in steroid-sensitive cells is their inevitable progression to a steroid-insensitive state; current therapies are based on the assumption that hormone insensitivity is associated with loss of receptor. We demonstrate for the first time that breast tumor cells can progress to steroid insensitivity in spite of functional steroid receptors. Transfection of the steroid-inducible LTR-C3 gene into unresponsive S115 mouse mammary tumor cells results in full inducibility of that gene with both androgen and glucocorticoid. Thus, although all known endogenous inducible parameters are lost, the steroid sensitivity of a transfected exogenous gene demonstrates that the machinery for steroid responsiveness is still fully functional. Furthermore, these transfected genes retain steroid sensitivity only while steroid is present; on prolonged withdrawal of steroid, they lose responsiveness, implying an epigenetic mechanism is involved.