Abstract 2558: MYC-dependent transformation model of triple-negative breast cancer in vivo

Recent comprehensive breast cancer studies examining mutations and genomic alterations have determined that deregulation of MYC and the PI3K pathway occur frequently during breast cancer progression and may be useful targets for therapy. As a result, there have been large efforts to develop PI3K, AKT and mTOR inhibitors (PAM inhibitors) for clinical use, however clinical trial data demonstrates that many patients treated with PAM inhibitors develop resistant disease. An alternative strategy would be to target Myc, though a lack of effective and specific inhibitors makes this difficult. To identify the core vulnerabilities in these cancers we developed an in vivo xenograft model of triple-negative breast cancer driven by deregulated PI3K signaling and MYC. We hypothesize that determining how these pathways co-operate to transform normal human breast cells into breast carcinomas will reveal a tumor progression signature and highlight new therapeutic opportunities. We developed our model using the spontaneously immortalized, basal, triple-negative MCF10A cell line. By expressing the hotspot PIK3caH1047R protein alone in MCF10A cells (MCF10.H) in addition to MYC (MCF10.HM), we can model normal/early breast cancer and invasive ductal carcinoma respectively. This is the first in vivo human model of breast cancer dependent on MYC for transformation. When injected into female NOD-SCID mice, MCF10A.H cells form organized acinar ducts embedded in extracellular matrix. MCF10A.H ducts form with hollow lumen and a single layer of myoepithelial cells, recapitulating normal human breast histology. Alternatively, MCF10A.HM cells grow as high-grade carcinomas indicative of invasive disease. MCF10A.H benign growths and MCF10A.HM tumors remain basal-like and triple-negative by immunohistochemistry. Importantly, MCF10A.HM tumors are sensitive to MYC repression and therefore may be a suitable model to evaluate direct and indirect anti-MYC therapies. Having relevant human xenograft samples representing both normal and IDC tissue, we performed RNA-seq to identify a MYC-signature driving breast cancer transformation. Our current work will involve targeting the resulting MYC-driven pathways identified by RNA-seq to therapeutically target MYC in breast cancer. Citation Format: Corey Lourenco, Manpreet Kalkat, Dharmesh Dingar, Jason De Melo, Rosemary Yu, Linda Penn. MYC-dependent transformation model of triple-negative breast cancer in vivo [abstract]. In: Proceedings of the America