Reference SummaryLam JB, PLoS ONE 2009;4(3):e4968

Title

 Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.

Authors

 Lam JB; Chow KH; Xu A; Lam KS; Liu J; Wong NS; Moon RT; Shepherd PR; Cooper GJ; Wang Y

Journal

 PLoS ONE

Volume

 4

Issue

 3

Year

 2009

Pages

 e4968

Abstract

 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.

Links

 J:147458 – MGI References
19319191 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6.Cg-Adipoqtm1Chan/+ Tg(MMTV-PyVT)634Mul FVB/N-Tg(MMTV-PyVT)634Mul/J mice were crossed with adiponectin knockout mice. Mice were subsequently backcrossed to C57BL/6J for 12 generations.
B6.Cg-Tg(MMTV-PyVT)634Mul FVB/N-Tg(MMTV-PyVT)634Mul/J mice were crossed with adiponectin knockout mice. Mice were subsequently backcrossed to C57BL/6J for 12 generations.
FVB.Cg-Adipoqtm1Chan/+ Tg(MMTV-PyVT)634Mul FVB/N-Tg(MMTV-PyVT)634Mul/J mice were crossed with adiponectin knockout mice. Mice were subsequently backcrossed to FVB/N for 12 generations.
FVB.Cg-Tg(MMTV-PyVT)634Mul FVB/N-Tg(MMTV-PyVT)634Mul/J mice were crossed with adiponectin knockout mice. Mice were subsequently backcrossed to FVB/N for 12 generations.
FVB/N-Tg(MMTV-PyVT)634Mul/J These mice were from The Jackson Laboratory.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB.Cg-Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
FVB.Cg-Adipoqtm1Chan/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
B6.Cg-Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
B6.Cg-Adipoqtm1Chan/+ Tg(MMTV-PyVT)634Mul Mammary gland tumor Mammary gland

100
[not specified] Mammary gland tumor Mammary gland

0
[not specified]-Adipoqtm1Chan/+ Mammary gland tumor Mammary gland

0
FVB/N-Tg(MMTV-PyVT)634Mul/J Mammary gland tumor Mammary gland

100