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Cancer Res. 2018 Jul 15;78(14):3877-3887. doi: 10.1158/0008-5472.CAN-17-2892. Epub 2018 Jun 29.

Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland.

Author information

1
Department of Pathology and Massey Cancer Center, Virginia Commonwealth University Health System, Richmond, Virginia.
2
Department of Pathology, Northwestern University, Chicago, Illinois.
3
Department of Pathology and Massey Cancer Center, Virginia Commonwealth University Health System, Richmond, Virginia. charles.clevenger@vcuhealth.org.

Abstract

The prolyl isomerase cyclophilin A (CypA) regulates the Jak2/Stat5 pathway, which is necessary for mammary differentiation and the pathogenesis of breast cancer. In this study, we assessed the role of this isomerase during mammary gland development and erbB2-driven tumorigenesis. Genetic deletion of CypA resulted in delayed mammary gland morphogenesis and differentiation with corresponding decrease in Jak2/Stat5 activation; mammary gland cross-transplantation confirmed this defect was epithelial in nature. Analysis of mammary stem and progenitor populations revealed significant disruption of epithelial maturation. Loss of CypA in the erbB2 transgenic mouse model revealed a marked increase in mammary tumor latency that correlated with decreased Stat5 activation, associated gene expression, and reduced epithelial cell proliferation. These results demonstrate an important role for CypA in the regulation of Jak2/Stat5-mediated biology in mammary epithelium, identifying this isomerase as a novel target for therapeutic intervention.Significance: These findings reveal cyclophilin A functions in normal mammary epithelial development and ErbB2-driven mammary tumorigenesis and suggest therapies targeting cyclophilin A may be efficacious for breast cancer treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3877/F1.large.jpg Cancer Res; 78(14); 3877-87. ©2018 AACR.

PMID:
29959151
PMCID:
PMC6050080
[Available on 2019-07-15]
DOI:
10.1158/0008-5472.CAN-17-2892

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