The ratio of estrogen receptor β (ERβ) to ERα can alter the estrogen-like properties of tamoxifen. Transient transfection of ERβ cDNA into cells can decrease the estrogen-like properties of the ERα:tamoxifen complex, whereas an increase in the amount of ERβ is associated with tamoxifen-resistant breast cancer. We have addressed each of these hypotheses by examining well characterized laboratory models. We determined whether changes in endogenous ERβ are responsible for the estrogen-like or antiestrogenic properties of tamoxifen or raloxifene in MDA-MB-231 cells transfected with cDNAs for ERα or mutants D351G, D351Y. We found that the amount of ERβ mRNA in separate, stable transfectants of mutant ERα cDNA was always <2% of ERα. Since at least a 50:50 mixture of ERα:ERβ is needed to silence the tamoxifen:ERα complex, we conclude that insufficient ERβ mRNA is available for selective ER modulation in stable transfectants of D351G and D351Y ERα. Similarly, to test the hypothesis that ERβ is up-regulated and plays an important role during the development of tamoxifen-stimulated tumor growth, we quantitatively analyzed ERβ and ERα mRNA in tamoxifen-naïve (MCF-7:E2, ECC1:E2) and tamoxifen-stimulated tumors (MCF-7:TAM, EnCa 101:TAM). We found that ERβ mRNA levels were not significantly elevated in tamoxifen-stimulated tumors and the ERα mRNA remained over 99% out of all ER species for all the tumors tested. The same results were also obtained when mRNA levels of ERβ and ERα in a series of tamoxifen-naïve and tamoxifen-resistant breast cancer was analyzed. We conclude that endogenous ERβ may not play a dominant role in the modulation of the tamoxifen ERα complex, or in the development of tamoxifen-stimulated resistant tumor growth.

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