p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis

• Published in: Oncogene Vol. 32; no. 18; pp. 2292 - 2303
• Main Authors: Qian, X, Hulit, J, Suyama, K, Eugenin, E A, Belbin, T J, Loudig, O, Smirnova, T, Zhou, Z N, Segall, J, Locker, J, Phillips, G R, Norton, L, Hazan, R B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-05-2013; Nature Publishing Group
• Subjects: 631/136/2091; 631/67/1347; 631/67/322; 631/80/84/2336; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell cycle; Cell growth; Cell Movement - genetics; Cell Proliferation; Cyclin E; Cyclin E - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclins; Cytoskeleton; Cytoskeleton - genetics; Cytoskeleton - metabolism; Development and progression; Female; G1 Phase Cell Cycle Checkpoints - genetics; Gene Knockout Techniques; Human Genetics; Humans; Internal Medicine; Mammary gland; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Transgenic; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Oncology; original-article; Physiological aspects; Tumors; cyclin E; invasion; cell cycle; cytoskeleton; metastasis; p21CIP1; breast cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.249

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.