Inhibition of mammary tumor growth by estrogens: is there a specific role for estrogen receptors alpha and beta?
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 ERα 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 regression. 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 up-regulated 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.
Soldati
Rocío
R
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine, National Research Council of Argentina (CONICET), 1428 Buenos Aires, Buenos Aires, Argentina.
Wargon
Victoria
V
Cerliani
Juan Pablo
JP
Giulianelli
Sebastián
S
Vanzulli
Silvia Inés
SI
Gorostiaga
María Alicia
MA
Bolado
Julieta
J
do Campo
Pablo
P
Molinolo
Alfredo
A
Vollmer
Günter
G
Lanari
Claudia
C
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D011422:Propionates
D018931:Antineoplastic Agents, Hormonal; D051033:Apoptosis Inducing Factor; D053453:Caspase 9; D019938:Cyclin D1; D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; D011980:Receptors, Progesterone; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; C530105:Ccnd1 protein, mouse; C494830:AIFM1 protein, mouse; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; C506434:Casp9 protein, mouse