Abstract
Abstract Basal-like carcinoma is a subtype of breast cancer that is characterized by poor prognosis and high intratumor heterogeneity. In basal-like breast epithelia, we have identified two anticorrelated gene-expression programs that arise among single extracellular matrix (ECM)-attached cells during organotypic 3D culture. The first program contains multiple TGFβ-related genes including TGFBR3, and its heterogeneous induction is critical to suppress ductal branching. The second program contains JUND together with the basal-like marker, KRT5. Homogenizing JUND expression in single cells leads to 3D acini with bridged lumina that are similar to cribiform ductal carcinoma in situ. TGFBR3 and JUND together comprise a circuit that is interconnected via four negative-feedback loops. Computational modeling of the circuit predicts damped, antiphase oscillations upon stimulation with endogenous impulses of TGFβ-like ligand, and we directly observe these spontaneous responses in 3D culture by live-cell imaging. The TGFBR3-JUND circuit is remarkably conserved in early basal-like tumors that heterogeneously express KRT5, suggesting that asynchronous circuit dynamics are active in this patient subset. We further show that the circuit is strongly dependent on ECM engagement, as detachment leads to a rewiring that is triggered by RPS6 dephosphorylation and maintained by juxtacrine signaling from tenascin C. Breast tumor heterogeneity need not stem from partial basal-like differentiation and could instead reflect dynamic toggling of individual cells between expression states. Citation Format: Chun-Chao Wang, Leen Jamal, Sameer S. Bajikar, Kristen A. Atkins, Kevin A. Janes. Single-cell gene-expression programs and basal-like breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5225. doi:10.1158/1538-7445.AM2013-5225
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