Abstract B43: ADAM12 is a novel regulator of stem-like cells in triple-negative breast cancer

Abstracts: AACR Special Conference on Tumor Metastasis; November 30-December 3, 2015; Austin, TX High expression of metalloprotease ADAM12 is associated with increased metastasis in triple-negative breast cancers (TNBC) and is an independent prognostic factor of chemoresistance in TNBC. ADAM12 is up-regulated in the claudin-low subtype of breast tumors and in the mesenchymal stem-like subtype of TNBC. Furthermore, expression of ADAM12 is elevated in post-therapy tumors. The goal of our study was to examine whether ADAM12 may serve as a marker or a therapeutic target in cells with enhanced metastatic cancer stem cell phenotype, using two representative TNBC cell lines with aggressive and metastatic phenotype, SUM159PT and Hs578T. We found that sorted cell subpopulations with the highest cell surface expression of ADAM12 had increased expression of cancer stem cell markers, decreased proliferation rates in 2-D cultures, and increased ability to form mammospheres under suspension conditions. ADAM12 knockdown decreased mammosphere formation, increased apoptotic cell death upon detachment, and decreased cell migration and invasion. ADAM12 knockdown also decreased the population of CD44+/CD24- cells and ALDEFLUOR+ cells and reduced tumor formation in mice in vivo, suggesting that ADAM12 might be necessary for maintaining cancer stem cell phenotype of TNBC cells. To get insight into molecular pathways modulated by ADAM12, we performed RNA sequencing in cells with inducible knockdown of ADAM12 and identified several candidate pathways. Our results indicate that ADAM12 is a novel regulator of the plasticity of TNBC stem cells and it may serve as a future target in anti-metastatic breast cancer therapies. Citation Format: Yue Qi, Sara Duhachek-Muggy, Hui Li, Linda Alyahya, Randi Wise, Anna Zolkiewska. ADAM12 is a novel regulator of stem-like cells in triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B43.