Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1.
Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1.
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DOI：
10.1158/2159-8290.cd-12-0292
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发表时间：
2013-02
期刊：
影响因子：
28.2
通讯作者：
Westermarck J
中科院分区：
文献类型：
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作者：
Laine A;Sihto H;Come C;Rosenfeldt MT;Zwolinska A;Niemelä M;Khanna A;Chan EK;Kähäri VM;Kellokumpu-Lehtinen PL;Sansom OJ;Evan GI;Junttila MR;Ryan KM;Marine JC;Joensuu H;Westermarck J
衰老诱导有助于癌症治疗反应，并且对于 p53 介导的肿瘤抑制至关重要。然而，p53 失活是否会主动抑制衰老诱导尚不清楚。在这里，我们证明，由于 p53 或 p21 失活，E2F1 过度表达会促进人癌蛋白 CIP2A 的表达，而 CIP2A 反过来又通过抑制 PP2A 活性，增加 E2F1 的稳定丝氨酸 364 磷酸化。多项证据表明，E2F1-CIP2A 反馈活性的增加使乳腺癌细胞对衰老诱导具有抵抗力。重要的是，在 CIP2A 缺陷的小鼠模型中，乳腺肿瘤发生受到损害，并且 CIP2A 缺陷的肿瘤显示出衰老诱导的标志物。此外，高 CIP2A 表达预示着接受衰老诱导化疗的乳腺癌患者亚组预后不良。这些结果表明 E2F1-CIP2A 反馈环路是乳腺癌细胞对衰老诱导敏感性的关键决定因素。它还构成了用于治疗 p53-p21 通路失活的癌症的有前景的促衰老靶标。
Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here we demonstrate that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence demonstrate that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A deficient mouse model, and CIP2A deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of breast cancer patients treated with senescence-inducing chemotherapy. Together these results implicate E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. It also constitutes a promising pro-senescence target for therapy of cancers with inactivated p53-p21 pathway.