Upregulation of AIB1, aromatase and ER alpha provides long-term estrogen-deprived human breast cancer cells with a mechanistic growth advantage for survival

To investigate the mechanisms by which breast cancer cells adapt and are able to grow during estrogen deprivation, human estrogen receptor-alpha(ER alpha)-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca) were cultured in steroid-depleted medium for 6-8 months until they started proliferating. Compared with the parental MCF-7Ca cells, long-term estrogen-deprived UMB-1Ca cells exhibited increased aromatase activity (2000%), AIB1 expression (3500%) and ERa expression (100%). When MCF-7Ca cells were isolated from tumors of mice treated for 12 months with an aromatase inhibitor, letrozole, ERa was reduced (50%) whereas AIB1 levels were increased (>1000%), suggesting that the mechanism of estrogen deprivation might predetermine the signaling pathway utilized. To a lesser extent long-term estrogen-deprived MCF-7 cells (LTED) displayed an increase in AIB1, ER alpha and aromatase activity. Consistent with other findings, the growth of the LTED cells was inhibited by estradiol and antiestrogens, whereas the UMB-1Ca cells were slightly stimulated by estradiol and inhibited by antiestrogens and letrozole. In LTED cells treated with estradiol, levels of AIB1 and ERa (95%) were reduced. Interestingly, estradiol treatment caused no change in AIB1 and ER alpha expression in the UMB-1Ca cells which might explain the differential growth effect of the cells to estradiol. Together, these results demonstrate that estrogen deprivation results in the upregulation of the estrogen signaling pathway at the level of AIB1, ER alpha and aromatase, which might attenuate ER-mediated transcription representing one mechanism by which tumors adapt to proliferation in a low estrogenic environment.