Inhibition of mammary tumor growth by estrogens: Is there a specific role for estrogen receptors alpha and beta?

Abstract

To evaluate the extent to which each estrogen receptor (ER) subtype contributes to the stimulation or to the inhibition of mammary tumor growth, we evaluated the effects of specific agonists in MC4-L2 cells, which are stimulated by 17β-estradiol (E 2), and in mammary carcinomas of the MPA mouse breast cancer model, which are inhibited by E 2. Both express ERα and ERβ. In MC4-L2 cells, 4,4,4-(4-propyl-(1H)-pyrazole-1,3,5- Triyl)trisphenol (PPT; ERα agonist) and (4-hydroxy-phenyl)-propionitrile (DPN; ERβ agonist) stimulated cell proliferation, whereas the opposite occurred in C4-HI primary cultures. The inhibitory effect was associated with a decrease in ERa and cyclin D1 expression and an increase in progesterone receptor (PR) expression as well as in the Bax/Bcl-xl ratio. In vivo, mice carrying C4-HI or 32-2-HI tumors were treated with E 2, PPT or DPN (3 mg/kg/day) or with vehicle. PPT and DPN inhibited tumor size, as did E 2, during the first 72 h. After a few days, DPN-Treated tumors started to grow again, while PPT-Treated tumors remained quiescent for a longer period of time. A pronounced decrease in the mitotic index and an increase in the apoptotic index was associated with tumor regresion. All treated tumors showed: (a) an increase in integrin α6 and Bax expression, (b) an increased stromal laminin redistribution, and (c) a decrease in ERα, Bcl-xl and Bcl-2 expression (P<0.001). Apoptosis-inducing factor (Aif) expression was increased in DPN-Treated tumors, while active caspase 9 was upregulated in PPT-Treated mice, demonstrating the involvement of the intrinsic apoptotic pathway in estrogen-induced regression in this model. In conclusion, our data indicate that although there may be some preferences for activation pathways by the different agonists, the stimulatory or inhibitory effects triggered by estrogens are cell-context dependent rather than ER isoform dependent. © Springer Science+Business Media, LLC. 2009.