Rebecca Cook
Faculty Member
Last active: 4/15/2019

ErbB2/Neu-induced, cyclin D1-dependent transformation is accelerated in p27-haploinsufficient mammary epithelial cells but impaired in p27-null cells.

Muraoka RS, Lenferink AE, Law B, Hamilton E, Brantley DM, Roebuck LR, Arteaga CL
Mol Cell Biol. 2002 22 (7): 2204-19

PMID: 11884607 · PMCID: PMC133673 · DOI:10.1128/mcb.22.7.2204-2219.2002

ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27(+/-) primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27(+/+) cells. In contrast, ErbB2- or cyclin D1-overexpressing p27(-/-) cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27(-/-) cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27(+/+), p27(+/-), and p27(-/-) cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27(+/-) mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27(+/+) glands. However, MMTV-neu/p27(-/-) glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27(+/+) glands. These results suggest that p27(+/-) mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

MeSH Terms (26)

Active Transport, Cell Nucleus Amino Acid Sequence Animals Apoptosis Base Sequence Cell Cycle Proteins Cell Division Cell Nucleus Cell Transformation, Neoplastic Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases Cyclin D1 Flow Cytometry Gene Deletion Gene Dosage Mammary Glands, Animal Mammary Neoplasms, Experimental Mice Mice, Knockout Molecular Sequence Data Proto-Oncogene Proteins Receptor, ErbB-2 RNA, Messenger Tumor Cells, Cultured Tumor Suppressor Proteins

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