pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia

Karl Simin, Hua Wu, Lucy Lu, Dan Pinkel, Donna Albertson, Robert Cardiff, Terry Van Dyke

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Retinoblastoma 1 (pRb) and the related pocket proteins, retinoblastoma-like 1 (p107) and retinoblastoma-like 2 (p130) (pRbf, 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 pRbf 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 pRbf function; Rbf inactivation by T 121, a fragment of SV40 T antigen that binds to and inactivates pRbf 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.

Original languageEnglish (US)
JournalPLoS Biology
Volume2
Issue number2
DOIs
StatePublished - Sep 27 2004

Fingerprint

breasts
Tumors
Retinoblastoma-Like Protein p107
inactivation
Breast
epithelium
Epithelium
Apoptosis
apoptosis
neoplasms
Cells
cell cycle
Aberrations
Cell Cycle
Retinoblastoma
Brain
Human Mammary Glands
Neoplasms
mammary glands
cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. / Simin, Karl; Wu, Hua; Lu, Lucy; Pinkel, Dan; Albertson, Donna; Cardiff, Robert; Van Dyke, Terry.

In: PLoS Biology, Vol. 2, No. 2, 27.09.2004.

Research output: Contribution to journalArticle

Simin, Karl ; Wu, Hua ; Lu, Lucy ; Pinkel, Dan ; Albertson, Donna ; Cardiff, Robert ; Van Dyke, Terry. / pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. In: PLoS Biology. 2004 ; Vol. 2, No. 2.
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