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The absence of estrogen receptors in breast cancer cells does not always imply that a patient will not respond to tamoxifen.

There is evidence that tamoxifen also inhibits 8 to 15 percent of hormone-independent or estrogen-receptor-negative breast cancer cells. Some physicians report responses in patients who supposedly are estrogen receptor negative; however, the doctors believe that these patients probably do have estrogen receptors that for some reason are not being detected, either because of their low number or perhaps because they are functionally different in some way from normal estrogen receptors. Alternatively, the clinical responses noted in these patients have led some to believe that tamoxifen may also work by some mechanism other than blockage of the estrogen receptor.

In fact, several groups of researchers have demonstrated that there may be more than one kind of estrogen receptor. Receptors that differ from the normal type are called variant estrogen receptors. Some appear to result when a normal gene for a receptor is erroneously copied, first into a messenger-RNA variant and then into a variant receptor protein with altered or defective function. Other variant estrogen receptors have been identified, suggesting that they may occur in many forms. If their presence in certain patients is not recognizable by current techniques, this fact would explain why some estrogen-receptor-negative patients nevertheless benefit from tamoxifen.