JCI - The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling

The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling

Dana M. Brantley-Sieders, Guanglei Zhuang, Donna Hicks, Wei Bin Fang, Yoonha Hwang, Justin M.M. Cates, Karen Coffman, Dowdy Jackson, Elizabeth Bruckheimer, Rebecca S. Muraoka-Cook, Jin Chen

Published in Volume 118, Issue 1

J Clin Invest. 2008; 118(1):64–78 doi:10.1172/JCI33154

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Figure 1

EphA2 deficiency reduces mammary tumorigenesis, metastasis, proliferation, and vascularity in MMTV-Neu mice.

(A) Number of surface lung lesions was significantly reduced in EphA2^–/– MMTV-Neu mice (P < 0.05; single-factor ANOVA). Data are mean ± SEM. (B) Top: Whole-mount mammary gland preparations (8 mo) revealed diminished hyperplasia in EphA2^–/– glands relative to controls. Shown are an EphA2^+/+ gland with pervasive epithelial hyperplasia (left) and an EphA2^+/– gland with a small tumor (arrowhead; middle). Asterisks indicate inguinal lymph node. Bottom: H&E-stained mammary gland sections (8 mo) reveal reduced epithelial cell content in EphA2^–/– MMTV-Neu tissue samples relative to controls. Scale bar: 250 μm. (C) Top: Mammary epithelial proliferation (PCNA⁺ nuclei; arrowheads), was significantly reduced (P < 0.05; 2-tailed, paired Student’s t test). Scale bar: 50 μm. Bottom: Mammary epithelial apoptosis (TUNEL⁺ nuclei; arrowheads) was not affected. (D) Top: Proliferation of primary mammary epithelial cells from EphA2^–/– animals (BrdU incorporation; arrowheads) was reduced relative to EphA2^+/+ cells (P < 0.05; 2-tailed, paired Student’s t test). Bottom: Apoptosis (TUNEL⁺ nuclei; arrowheads) was significantly increased in EphA2^–/– primary mammary epithelial cells relative to controls (P < 0.05; 2-tailed, paired Student’s t test). Scale bar: 20 μm. (E) H&E-stained tumor sections (1 yr) demonstrate increased cystic degeneration and lumen formation in EphA2^–/– tumors. Scale bar: 250 μm. (F) Decreased tumor cell proliferation (PCNA⁺ nuclei; arrowheads) was observed for EphA2^–/– MMTV-Neu tumors compared with controls (P < 0.05; single-factor ANOVA). Scale bar: 50 μm. (G) Microvascular density (CD31⁺ vessels; arrowheads) was significantly reduced in EphA2^–/– MMTV-Neu tumors relative to controls (P < 0.05; single-factor ANOVA). Scale bar: 100 μm.