While the lack of estrogen receptors would be the obvious cause for resistance to endocrine ther- apy, another potential mechanism is the mutational alteration in the estrogen-receptor gene that prevents the normal interaction of the hormone with its receptor. Interestingly, genetic variants in estrogen receptors have been found in normal breast tissue (Leygue et al., 1996). Many of these variants appear to be the result of various splicing differences in the formation of the mes- senger RNA for the receptor protein (cf. Miksicek, 1994). Although there has never been a clear association with altered estrogen receptors and the responsiveness to endocrine therapy, some preliminary data suggest that this might be true (Raam et al., 1988). There are, however, other potential changes in the cell that may lead to the resistance of the neoplastic cell to endocrine therapy, as noted in Figure 18.3. It is quite likely that the development of hormone resistance as the stage of progression continues is multifactorial, involving changes in more than one of the various potential alterations seen in Figure 18.3.
Steroid Receptors in Neoplasms Other Than Those of Mammary Origin
Steroid-receptor proteins have also been studied and found in other neoplasms (Stedman et al.,
1980). A number of such examples are seen in Table 18.2. Although this table is by no means complete, it does give the reader an indication that these various receptor proteins are expressed in a wide variety of neoplasms in the human as well as some in the animals that have been stud- ied. In the case of hepatocellular adenomas and renal neoplasms in the rat, both associated with
Figure 18.3 Potential multifactorial resistance to hormones of breast neoplasms. Resistance to the hor- mone may occur by changes at the level of the ligand, receptor, or a variety of other effectors. (Adapted from Hansen and Fuqua, 1999, with permission of the authors and publisher.)
estrogen administration, virtually all of these neoplasms, as might be expected, contain estro- gen-receptor proteins (cf. Schmid et al., 1985; Anderson et al., 1979).
With this knowledge, it was logical to try to determine whether or not those neoplasms possessing steroid receptors might be responsive to the effects of doses of the steroid or anti- steroid. There have been several attempts to treat specific neoplasms containing estrogen recep- tors, such as hepatocellular carcinomas and melanomas, with antiestrogens; the most successful of these have been attempts relating steroid receptor protein content with responses to antiandro- gens or estrogens in prostate cancer (Sadi and Barrack, 1994) and glucocorticoid receptors to corticosteroid responses in lymphatic leukemias (cf. Homo-Delarche, 1984). However, in nei- ther of these conditions has the determination of steroid-binding proteins been successfully re- lated to the effectiveness of therapy to the same degree that estrogen- and progesterone-receptor content has been related to the therapy of breast cancer.