P21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis

X. Qian, J. Hulit, K. Suyama, Eliseo Eugenin, T. J. Belbin, O. Loudig, T. Smirnova, Z. N. Zhou, J. Segall, J. Locker, G. R. Phillips, L. Norton, R. B. Hazan

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Cell proliferation and invasion are critical for malignant progression, yet how these processes relate to each other and whether they regulate one another during metastasis is unknown. We show that invasiveness of breast cancer cells is associated with growth arrest due to p21CIP1 upregulation. Knockdown of p21CIP1 increases cell proliferation and suppresses invasion. Since p21CIP1 acts to inhibit cyclin E during cell-cycle progression, we demonstrated that a constitutively active form of cyclin E had similar effects to p21CIP1 inhibition resulting in enhanced cell growth and suppressed invasiveness. We tested these findings in vivo in the Polyoma middle T mammary tumor model in which p21CIP1 was deleted. p21CIP1 knockout mice exhibited dramatic suppression of metastasis, independent of tumor growth, which was rescued by p21CIP1. Metastasis suppression by p21CIP1 ablation was associated with striking cytoskeletal reorganization leading to a non-invasive and highly proliferative state. Thus, p21CIP1 regulates metastasis by mediating reciprocal switching between invasion and proliferation.

Original languageEnglish (US)
Pages (from-to)2292-2303
Number of pages12
JournalOncogene
Volume32
Issue number18
DOIs
StatePublished - May 2 2013
Externally publishedYes

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Keywords

  • breast cancer
  • cell cycle
  • cyclin E
  • cytoskeleton
  • invasion
  • metastasis
  • p21CIP1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Qian, X., Hulit, J., Suyama, K., Eugenin, E., Belbin, T. J., Loudig, O., Smirnova, T., Zhou, Z. N., Segall, J., Locker, J., Phillips, G. R., Norton, L., & Hazan, R. B. (2013). P21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis. Oncogene, 32(18), 2292-2303. https://doi.org/10.1038/onc.2012.249