Academic Journal
pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia.
| Title: | pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. |
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| Authors: | Karl Simin, Hua Wu, Lucy Lu, Dan Pinkel, Donna Albertson, Robert D Cardiff, Terry Van Dyke |
| Source: | PLoS Biology, Vol 2, Iss 2, p E22 (2004) |
| Publisher Information: | Public Library of Science (PLoS), 2004. |
| Publication Year: | 2004 |
| Collection: | LCC:Biology (General) |
| Subject Terms: | Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1544-9173 1545-7885 |
| Relation: | https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885 |
| DOI: | 10.1371/journal.pbio.0020022 |
| Access URL: | https://doaj.org/article/368c23be1c4140f3adfd3d880e397868 |
| Accession Number: | edsdoj.368c23be1c4140f3adfd3d880e397868 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 15449173 15457885 |
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| DOI: | 10.1371/journal.pbio.0020022 |
| Published in: | PLoS Biology |
| Language: | English |