Mutations in functional domains of steroid and thyroid hormone receptors cause these molecules to become constitutive (hormone independent) transactivators of gene transcription. Mutations in, for example, the estrogen receptor (ER) may contribute to the loss of estrogen control of some breast carcinomas. The crucial factor in determining estrogen requirement for the growth of tumors may not be the presence or absence of estrogen-regulated ER, but whether the ERs present require estrogen to be able to cause transcription activation of growth regulatory genes. This also has implications for the therapy of breast cancer because it may be necessary to design effective anticancer agents to suppress the malignant effects of ER mutants.