Reference SummarySimin K, PLoS Biol 2004 Feb;2(2):E22

Title

 pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia.

Authors

 Simin K; Wu H; Lu L; Pinkel D; Albertson D; Cardiff RD; Dyke TV

Journal

 PLoS Biol

Volume

 2

Issue

 2

Year

 2004

Pages

 E22

Abstract

 Retinoblastoma 1 (pRb) and the related pocket proteins, retinoblastoma-like 1 (p107) and retinoblastoma-like 2 (p130) (pRb(f), collectively), play a pivotal role in regulating eukaryotic cell cycle progression, apoptosis, and terminal differentiation. While aberrations in the pRb-signaling pathway are common in human cancers, the consequence of pRb(f) loss in the mammary gland has not been directly assayed in vivo. We reported previously that inactivating these critical cell cycle regulators in divergent cell types, either brain epithelium or astrocytes, abrogates the cell cycle restriction point, leading to increased cell proliferation and apoptosis, and predisposing to cancer. Here we report that mouse mammary epithelium is similar in its requirements for pRb(f) function; Rb(f) inactivation by T(121), a fragment of SV40 T antigen that binds to and inactivates pRb(f) proteins, increases proliferation and apoptosis. Mammary adenocarcinomas form within 16 mo. Most apoptosis is regulated by p53, which has no impact on proliferation, and heterozygosity for a p53 null allele significantly shortens tumor latency. Most tumors in p53 heterozygous mice undergo loss of the wild-type p53 allele. We show that the mechanism of p53 loss of heterozygosity is not simply the consequence of Chromosome 11 aneuploidy and further that chromosomal instability subsequent to p53 loss is minimal. The mechanisms for pRb and p53 tumor suppression in the epithelia of two distinct tissues, mammary gland and brain, are indistinguishable. Further, this study has produced a highly penetrant breast cancer model based on aberrations commonly observed in the human disease.

Links

 J:88315 – MGI References
14966529 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6D2 "TgWAP-T121 mouse lines were maintained by crossing to nontransgenic B6D2F1 mice (Jackson Laboratory)".
B6D2-Tg(WAPT121)66Tvd "TgWAP-T121 mouse lines were maintained by crossing to nontransgenic B6D2F1 mice (Jackson Laboratory)".
C.Cg-Tg(WAPT121)66Tvd The mice used in this study were from backcross generations N6, N7, and N9.
[not specified]-Tg(WAPT121)66Tvd This cohort of mice was generated by mating male transgenic mice on an unspecified genetic background to female Trp53tm1Tyj/+ mice, also on an unspecified genetic background.
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj This cohort of mice was generated by mating male transgenic mice on an unspecified genetic background to female Trp53tm1Tyj/+ mice, also on an unspecified genetic background.
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ This cohort of mice was generated by mating male transgenic mice on an unspecified genetic background to female Trp53tm1Tyj/+ mice, also on an unspecified genetic background.
Visual Summary Grid

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Leukocyte lymphoma Thymus

observed
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj Leukocyte lymphoma Thymus

observed
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland adenocarcinoma Mammary gland

very high
[not specified]-Tg(WAPT121)66Tvd Mammary gland adenocarcinoma Mammary gland

high
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland adenocarcinoma - glandular Mammary gland

29
[not specified]-Tg(WAPT121)66Tvd Mammary gland adenocarcinoma - glandular Mammary gland

40
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland adenocarcinoma - solid Mammary gland

94
[not specified]-Tg(WAPT121)66Tvd Mammary gland adenocarcinoma - solid Mammary gland

50
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland carcinoma - spindle cell Mammary gland

0
[not specified]-Tg(WAPT121)66Tvd Mammary gland carcinoma - spindle cell Mammary gland

10
B6D2 Mammary gland tumor Mammary gland

0
B6D2-Tg(WAPT121)66Tvd Mammary gland tumor Mammary gland

100
C.Cg-Tg(WAPT121)66Tvd Mammary gland tumor Mammary gland

100
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland tumor Mammary gland

89 - 100
[not specified]-Tg(WAPT121)66Tvd Mammary gland tumor Mammary gland

93
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj Mammary gland tumor Mammary gland

0
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mammary gland tumor - pilar Mammary gland

0
[not specified]-Tg(WAPT121)66Tvd Mammary gland tumor - pilar Mammary gland

40
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed
[not specified]-Tg(WAPT121)66Tvd Trp53tm1Tyj (Unspecified organ) tumor (Unspecified organ)

100