Mechanisms of hormone independence in human breast cancer

The progression of human breast cancer from a hormone dependent to a hormone independent phenotype is a clinical problem which limits the long term usefulness of the relatively nontoxic endocrine therapies. It is also associated with a more aggressive form of the disease. Since expression of estrogen receptor-alpha appears to be relatively stable phenotype during breast cancer progression, the majority of breast tumors that develop hormone independence and resistance to endocrine therapies do so despite the continued expression of estrogen receptor-alpha. Several possible mechanisms that may contribute to the progression of breast cancer from hormone dependence to independence, either alone or in combination with other mechanisms, are reviewed. These include variant or mutated estrogen receptor-alpha, ligant independent activation of estrogen receptor-alpha, altered expression of down-stream estrogen target genes, post receptor and pharmacological alterations.