Simultaneous disruption of estrogen receptor and Wnt/β-catenin signaling is involved in methyl amooranin-mediated chemoprevention of mammary gland carcinogenesis in rats.
Methyl-amoorain (methyl-25-hydroxy-3-oxoo-lean-12-en-28-oate, AMR-Me), a novel synthetic oleanane triterpenoid, exerts a striking chemopreventive effect against 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis through antiproliferative and proapoptotic actions. Nevertheless, the underlying mechanisms of action remain to be established. As estrogen receptor (ER) and canonical Wnt/b-catenin signaling are involved in the development and progression of breast cancer, the current study was designed to investigate the effects of AMR-Me treatment on the expressions of ER-a, ER-b, b-catenin and cyclin D1 in rat mammary tumors induced by DMBA. Mammary tumor samples were harvested from an 18-week chemopreventive study in which AMR-Me (0.8–1.6 mg/kg) was shown to inhibit mammary carcinogenesis in a dose–response manner. The expressions of ER-a, ER-b, b-catenin, and cyclin D1 were determined by immunohistochemistry and reverse transcription-polymerase chain reaction. AMR-Me downregulated the expression of intratumor ER-a and ER-b and lowered the ratio of ER-a to ER-b. AMR-Me also reduced the expression, cytoplasmic accumulation, and nuclear translocation of b-catenin, the essential transcriptional cofactor for Wnt signaling. Furthermore, AMR-Me modulated the expression of cell growth regulatory gene cyclin D1, which is a downstream target for both ER and Wnt signaling. AMR-Me at 1.6 mg/kg for 18 weeks did not exhibit any hepatotoxicity or renotoxicity. The results of the present study coupled with our previous findings indicate that simultaneous disruption of ER and Wnt/b-catenin signaling possibly contributes to antiproliferative and apoptosis-inducing effects implicated in AMR-Me-mediated chemoprevention of DMBA-induced breast tumorigenesis in rats. Our results also suggest a possible crosstalk between two key regulatory pathways, namely ER and Wnt/b-catenin signaling, involved in mammary carcinogenesis and the value of simultaneously targeting these pathways to achieve breast cancer chemoprevention.
Animesh
A
Mandal
Deepak
D
Bhatia
Anupam
A
Bishayee
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D018890:Chemoprevention; D019938:Cyclin D1 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008321:Mammary Glands, Animal / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
C530106:Ccnd1 protein, rat; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D014315:Triterpenes; D051153:Wnt Proteins; C453733:amooranin; D051176:beta Catenin; D019938:Cyclin D1; D015127:9,10-Dimethyl-1,2-benzanthracene