Skip to main content
. Author manuscript; available in PMC: 2007 Mar 6.
Published in final edited form as: J Steroid Biochem Mol Biol. 2006 Nov 7;102(1-5):128–138. doi: 10.1016/j.jsbmb.2006.09.003

Fig. 9.

Fig. 9

Evolution of antihormonal resistance in laboratory models of breast cancer. Long-term antihormonal therapy leads to selection of resistant cells that are stimulated to grow by a SERM or grow in an estrogen-depleted environment (AI resistance). Based on prior laboratory studies (4–10, 12, 13) and data presented here, the progression of antihormonal resistance can be separated into at least 2 phases defined by different growth responses to E2 and FUL. In Phase I resistant disease, tumor cells are either growth stimulated by E2 (as in SERM resistance) or grow independently of E2 (as in estrogen withdrawn/AI resistance). However, these Phase I resistant cells remain dependent on ER since they are sensitive to growth inhibition by FUL. Selection of tumor cells continues during exhaustive antihormonal therapy until Phase II resistance develops, which is characterized by a new biology of E2 action. Both Phase II SERM and estrogen withdrawn-resistant tumors respond to E2 with growth inhibition and apoptosis. FUL still inhibits growth of Phase II SERM-resistant tumors, but not of Phase II estrogen withdrawn-resistant tumors. Moreover, FUL interacts with E2 at physiologic concentrations to promote growth of both Phase II SERM and estrogen withdrawn-resistant disease. These emerging concepts on the evolution of antihormonal resistance based on laboratory studies have important implications for the utility of estrogen and FUL in the clinic.