title: p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis.
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.
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: X
authors: X
authors: Qian
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: J
authors: J
authors: Hulit
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: K
authors: K
authors: Suyama
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: E A
authors: EA
authors: Eugenin
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: T J
authors: TJ
authors: Belbin
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: O
authors: O
authors: Loudig
authors: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: T
authors: T
authors: Smirnova
authors: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: Z N
authors: ZN
authors: Zhou
authors: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: J
authors: J
authors: Segall
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: J
authors: J
authors: Locker
authors: Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
authors: G R
authors: GR
authors: Phillips
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: L
authors: L
authors: Norton
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: R B
authors: RB
authors: Hazan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D055786:Gene Knockout Techniques; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*
chemical_list: C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21