Adiponectin Haploinsufficiency Promotes Mammary Tumor Development in MMTV-PyVT Mice by Modulation of Phosphatase and Tensin Homolog ActivitiesReport as inadecuate




Adiponectin Haploinsufficiency Promotes Mammary Tumor Development in MMTV-PyVT Mice by Modulation of Phosphatase and Tensin Homolog Activities - Download this document for free, or read online. Document in PDF available to download.

Background

Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.

Methodology-Principal Findings

In the present study, MMTV-polyomavirus middle T antigen MMTV-PyVT transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB-N and C57BL-6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase PI3K-Akt-beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog PTEN activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin Trx1 and thioredoxin reductase TrxR1 were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.

Conclusion

Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K-Akt signalling pathway through a mechanism involving Trx1-TrxR1 redox regulations.



Author: Janice B. B. Lam , Kim H. M. Chow , Aimin Xu, Karen S. L. Lam, Jing Liu, Nai-Sum Wong, Randall T. Moon, Peter R. Shepherd, Garth

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents