462

There is increasing interest in the proteasome inhibitor, bortezomib (PS341), as a breast cancer therapeutic. However, early clinical studies of bortezomib against unselected breast cancer cases have not shown broad activity as a single agent. This indicates a need for better preclinical understanding of this agent and mechanism against specific breast cancer phenotypes that may be most responsive. Furthermore, bortezomib may be more effective in combination with other breast cancer therapeutics, particularly those with complementary or synergistic mechanisms. To explore potential predictive biomarkers for bortezomib in breast cancer and the choice of targeted therapeutics for use in combination with bortezomib, we have studied a panel of seven breast cancer cell lines. ER and ErbB2 are validated targets whose overexpressed receptors are thought to be regulated by proteasomal decay, and this panel thus reflects four clinically relevant phenotypes: ER+/ErbB2- (MCF7, T47D), ER+/ErbB2+ (BT474, MCF7/HER2), ER-/ErbB2+ (SKBr3, MDA453), and ER-/ErbB2- (MDA231). Since the efficacy of bortezomib is known to relate in part to its inhibition of constitutively activated NFκB, we characterized the panel for p50 and p65 NFκB subunit DNA-binding activities. Bortezomib treatment (50 nM x 24 hr) downregulated nuclear expression of p50 and p65 as well as total NFκB DNA-binding activity. With the exception of MDA231, breast cancer cells with the highest endogenous p50 NFκB activity appeared most sensitive to this proteasome inhibitor; and inhibition of breast cancer growth by bortezomib (IC50 range: 3 - 20 nM) was most effective against the ER-/ErbB2+ phenotype. Interestingly, the tamoxifen (TAM)-resistant ER+/ErbB2+ phenotype showed restoration to a TAM-sensitive state when BT474 and MCF7/HER2 cells were treated with bortezomib in combination with TAM. These findings point to ErbB2+ breast cancers as being potentially more responsive to bortezomib monotherapy as compared to ER+ breast cancers, and suggest that the NFκB inhibiting activity of bortezomib may enhance the endocrine responsivness of ER+/ErbB2+ breast cancers.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]