Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Oncogene. 2013 May 2;32(18):2292-2303.e7. doi: 10.1038/onc.2012.249. Epub 2012 Jul 2.
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.
细胞增殖和侵袭对于恶性进展至关重要，但这些过程如何相互关联，以及它们在转移过程中是否相互调节尚不清楚。我们发现，乳腺癌细胞的侵袭性与由于 p21CIP1 上调而导致的生长停滞有关。p21CIP1 的敲低会增加细胞增殖并抑制侵袭。由于 p21CIP1 在细胞周期进展过程中抑制细胞周期蛋白 E，我们证明了一种组成性激活形式的细胞周期蛋白 E 具有与 p21CIP1 抑制相似的效果，导致细胞生长增强和侵袭性降低。我们在 Polyoma middle T 乳腺肿瘤模型中对这些发现进行了体内测试，其中 p21CIP1 被删除。p21CIP1 敲除小鼠表现出明显的转移抑制，与肿瘤生长无关，p21CIP1 可挽救转移抑制。p21CIP1 消融引起的转移抑制与显著的细胞骨架重排有关，导致非侵袭性和高增殖状态。因此，p21CIP1 通过介导侵袭和增殖之间的相互转换来调节转移。
