Abstract
In an effort to improve therapeutic tumor cell killing in luminal B breast cancers, we are investigating the combination of endocrine therapies with targeted inhibition of pro-survival proteins of the Bcl2 family, including Bcl2, Bcl-xL, and Mcl-1. Bcl2-family proteins are often overexpressed in breast cancers and are associated with tumor progression, therapeutic resistance, and poor patient survival. These proteins function by sequestering pro-apoptotic BH3-only proteins (BIM, BID, Noxa and Puma), thus inhibiting caspase-dependent apoptosis. We found Mcl1 gene amplification in 15/133 luminal B breast tumors (11%) curated through the Cancer Genome Atlas (TCGA), and Bcl2l1 (encoding Bcl-xL) gene amplification in 1/133 luminal B breast tumors, although Bcl2l1 mRNA was upregulated in 19/133 samples. Bcl2 was not amplified or overexpressed in TCGA-curated luminal B breast tumors. The BH3 mimetic ABT-263, which specifically binds Bcl2 and Bcl-xL, increased tumor cell killing in 3 out of 4 estrogen-deprived luminal B human breast cancer cell lines. However, ZR75-1 cells, which are Mcl1 gene amplified, were resistant to ABT-263. Further, Mcl-1 protein upregulation was induced in HCC-1428 and T47D cells treated with ABT-263, suggesting that cells may use Mcl-1 upregulation to partially mitigate the effects of Bcl-xL targeting with ABT-263. Mcl-1 knockdown using an shRNA approach, decreased cell growth and increased caspase-dependent apoptosis, and increased sensitivity to ABT-263 in 4 of the 4 cell lines tested, including ZR75-1 cells. We used long-term estrogen withdrawal (LTED) to model the sustained response of breast cancer cells to aromatase inhibitors (e.g., exemestane). As compared to parental breast cancer cell lines under estrogen withdraw conditions, LTED populations drastically increased protein levels of Mcl-1. Future experiments will be aimed at assessing the impact of Mcl-1 depletion on ABT-263-treated LTED populations. We predict that combined inhibition of Bcl-2, Bcl-xL and Mcl-1 will improve response of cells to estrogen deprivation. In summary, these preliminary studies suggest that BH3 mimetics targeting Bcl-2 family proteins may be therapeutically efficacious in endocrine-refractory luminal B breast tumors, and support future endeavors to generate BH3-mimetics specifically targeting Mcl-1.
Citation Format: Michelle M. Williams, Steve Fesik, Donna Hicks, Rebecca S. Cook. Targeting the antiapoptotic protein Mcl-1 in luminal B breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B071.
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