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Tytuł:
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Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217.
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Autorzy:
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Northey, Jason J.
Barrett, Alexander S.
Acerbi, Irene
Hayward, Mary-Kate
Talamantes, Stephanie
Dean, Ivory S.
Mouw, Janna K.
Ponik, Suzanne M.
Lakins, Jonathon N.
Po-Jui Huang
Junmin Wu
Quanming Shi
Samson, Susan
Keely, Patricia J.
Mukhtar, Rita A.
Liphardt, Jan T.
Shepherd, John A.
Hwang, E. Shelley
Yunn-Yi Chen
Hansen, Kirk C.
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Temat:
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BREAST cancer
MICRORNA
EPITHELIAL cells
CELL proliferation
COLLAGEN
PROTEIN metabolism
RNA metabolism
ANIMAL experimentation
BREAST
BREAST tumors
COMPARATIVE studies
RESEARCH methodology
MEDICAL cooperation
MICE
RESEARCH
TRANSFERASES
EVALUATION research
BLIND experiment
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Źródło:
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Journal of Clinical Investigation. Nov2020, Vol. 130 Issue 11, p5721-5737. 17p. 5 Color Photographs, 3 Graphs.
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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. [ABSTRACT FROM AUTHOR]
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