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Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.

Publication ,  Journal Article
Northey, JJ; Barrett, AS; Acerbi, I; Hayward, M-K; Talamantes, S; Dean, IS; Mouw, JK; Ponik, SM; Lakins, JN; Huang, P-J; Wu, J; Shi, Q ...
Published in: J Clin Invest
November 2, 2020

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 2, 2020

Volume

130

Issue

11

Start / End Page

5721 / 5737

Location

United States

Related Subject Headings

  • Trans-Activators
  • Risk Factors
  • RNA, Neoplasm
  • Proto-Oncogene Proteins c-akt
  • Oncogene Proteins
  • Middle Aged
  • MicroRNAs
  • Mice
  • Mammary Glands, Human
  • Immunology
 

Citation

APA
Chicago
ICMJE
MLA
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Northey, J. J., Barrett, A. S., Acerbi, I., Hayward, M.-K., Talamantes, S., Dean, I. S., … Weaver, V. M. (2020). Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217. J Clin Invest, 130(11), 5721–5737. https://doi.org/10.1172/JCI129249
Northey, Jason J., Alexander S. Barrett, Irene Acerbi, Mary-Kate Hayward, Stephanie Talamantes, Ivory S. Dean, Janna K. Mouw, et al. “Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.J Clin Invest 130, no. 11 (November 2, 2020): 5721–37. https://doi.org/10.1172/JCI129249.
Northey JJ, Barrett AS, Acerbi I, Hayward M-K, Talamantes S, Dean IS, et al. Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217. J Clin Invest. 2020 Nov 2;130(11):5721–37.
Northey, Jason J., et al. “Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.J Clin Invest, vol. 130, no. 11, Nov. 2020, pp. 5721–37. Pubmed, doi:10.1172/JCI129249.
Northey JJ, Barrett AS, Acerbi I, Hayward M-K, Talamantes S, Dean IS, Mouw JK, Ponik SM, Lakins JN, Huang P-J, Wu J, Shi Q, Samson S, Keely PJ, Mukhtar RA, Liphardt JT, Shepherd JA, Hwang ES, Chen Y-Y, Hansen KC, Littlepage LE, Weaver VM. Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217. J Clin Invest. 2020 Nov 2;130(11):5721–5737.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 2, 2020

Volume

130

Issue

11

Start / End Page

5721 / 5737

Location

United States

Related Subject Headings

  • Trans-Activators
  • Risk Factors
  • RNA, Neoplasm
  • Proto-Oncogene Proteins c-akt
  • Oncogene Proteins
  • Middle Aged
  • MicroRNAs
  • Mice
  • Mammary Glands, Human
  • Immunology