Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217
Jason J. Northey, Alexander S. Barrett, Irene Acerbi, Mary-Kate Hayward, Stephanie Talamantes, Ivory S. Dean, Janna K. Mouw, Suzanne M. Ponik, Jonathon N. Lakins, Po-Jui Huang, Junmin Wu, Quanming Shi, Susan Samson, Patricia J. Keely, Rita A. Mukhtar, Jan T. Liphardt, John A. Shepherd, E. Shelley Hwang, Yunn-Yi Chen, Kirk C. Hansen, Laurie E. Littlepage, Valerie M. Weaver
Jason J. Northey, Alexander S. Barrett, Irene Acerbi, Mary-Kate Hayward, Stephanie Talamantes, Ivory S. Dean, Janna K. Mouw, Suzanne M. Ponik, Jonathon N. Lakins, Po-Jui Huang, Junmin Wu, Quanming Shi, Susan Samson, Patricia J. Keely, Rita A. Mukhtar, Jan T. Liphardt, John A. Shepherd, E. Shelley Hwang, Yunn-Yi Chen, Kirk C. Hansen, Laurie E. Littlepage, Valerie M. Weaver
View: Text | PDF
Research Article Oncology

Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217

Abstract

Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness–repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density. Culture studies demonstrated that ZNF217 mediates a matrix stiffness– and collagen density–induced increase in Akt activity and mammary epithelial cell proliferation. Manipulation of the epithelium in a mouse model of mammographic density supported a causal relationship between stromal stiffness, reduced miR-203, higher levels of the murine homolog Zfp217, and increased Akt activity and mammary epithelial proliferation. ZNF217 was also increased in the normal breast epithelium of women with high mammographic density, correlated positively with epithelial proliferation and density, and inversely with miR-203. The findings identify ZNF217 as a potential target toward which preexisting therapies, such as the Akt inhibitor triciribine, could be used as a chemopreventive agent to reduce cancer risk in women with high mammographic density.

Authors

Jason J. Northey, Alexander S. Barrett, Irene Acerbi, Mary-Kate Hayward, Stephanie Talamantes, Ivory S. Dean, Janna K. Mouw, Suzanne M. Ponik, Jonathon N. Lakins, Po-Jui Huang, Junmin Wu, Quanming Shi, Susan Samson, Patricia J. Keely, Rita A. Mukhtar, Jan T. Liphardt, John A. Shepherd, E. Shelley Hwang, Yunn-Yi Chen, Kirk C. Hansen, Laurie E. Littlepage, Valerie M. Weaver

×

Figure 8

High ZNF217 expression and mammary epithelial cell proliferation are associated with high epithelial and mammographic density.

Options: View larger image (or click on image) Download as PowerPoint
High ZNF217 expression and mammary epithelial cell proliferation are ass...
(A) Immunohistochemical (IHC) staining of human breast tissue sections using a ZNF217-specific antibody. Scale bar: 100 μm. (B) Quantification of ZNF217 staining from A expressed as the percentage of highly positive epithelial nuclear area over total epithelial area (low MD, n = 20; high MD, n = 20). (C) IHC staining of human breast tissue sections using a phospho–histone H3–specific antibody. Scale bar: 100 μm. (D) Quantification of phospho–histone H3 staining from C expressed as the percentage of highly positive epithelial nuclear area over total epithelial area (low MD, n = 20; high MD, n = 20). (E) Correlation between ZNF217 staining quantified in B and epithelial density (n = 12). (F) Correlation between ZNF217 and miR-203 levels determined by qRT-PCR from the same human breast specimens (n = 11). (G) qRT-PCR analysis for ROBO1 using RNA isolated from human breast tissues (low MD, n = 9; high MD, n = 18). Results are normalized to 18S RNA. (H) The ratio of relative ZNF217/ROBO1 gene expression for 14 individual patient specimens with high MD. The dashed line represents a ratio of 1. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-tailed Mann-Whitney U test (B, D, and G).