Breast cancer represents the second leading cause of
cancer-related deaths among women worldwide and preventive
therapy could reverse or delay the devastating impact of this disease. Methyl-
amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me), a novel synthetic
oleanane triterpenoid, reduced the incidence and burden of
7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary
tumors in rats through antiproliferative and proapoptotic effects. Since chronic
inflammation plays an important role in the pathogenesis of
breast cancer and several synthetic
oleanane compounds are known potent
anti-inflammatory agents, we aim to investigate anti-inflammatory mechanisms of
AMR-Me by monitoring various proinflammatory and stress markers, such as
cyclooxygenase-2 (COX-2) and
heat shock protein 90 (HSP90), and nuclear factor-κB (NF-κB) signaling during DMBA mammary
tumorigenesis in rats. Mammary
tumors were harvested from a chemopreventive study in which
AMR-Me (0.8-1.6 mg/kg) was found to inhibit mammary
carcinogenesis in a dose-response manner. The expressions of COX-2, HSP90, NF-κB, and inhibitory κB-α (IκB-α) were determined by immunohistochemistry and reverse transcription-polymerase chain reaction.
AMR-Me downregulated the expression of intratumor COX-2 and HSP90, suppressed the degradation of IκB-α, and reduced the translocation of NF-κB from cytosol to nucleus. Our present study provides the first in vivo evidence that NF-κB-evoked inflammatory cascade is a major target of
AMR-Me in
breast cancer. Our current results together with our previous findings suggest that disruption of NF-κB signaling contributes to anti-inflammatory, antiproliferative, and apoptosis-inducing mechanisms involved in
AMR-Me-mediated
chemoprevention of rat mammary
carcinogenesis. These encouraging mechanistic results coupled with a safety profile should facilitate the clinical development of
AMR-Me as
breast cancer chemopreventive
drug.