Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Res. 2020 Apr 1;80(7):1486-1497. doi: 10.1158/0008-5472.CAN-19-3607. Epub 2020 Feb 14.
Invasive lobular carcinoma (ILC) accounts for 8%-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin-deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2-induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2-induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. SIGNIFICANCE: Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.
浸润性小叶癌（ILC）占所有乳腺癌病例的 8%-14%。ILC 的主要特征是细胞-细胞黏附蛋白 E-钙黏蛋白的功能丧失。然而，E-钙黏蛋白的单独缺失并不会使小鼠易患乳腺肿瘤的发生，这表明 ILC 的形成还需要其他的干扰。此前，我们发现 ASPP2 的 N 端截断变体（t-ASPP2）是 E-钙黏蛋白缺失的小鼠乳腺中 ILC 的驱动因素。在这里，我们表明 t-ASPP2 的表达诱导了肌动球蛋白的松弛，从而使 E-钙黏蛋白缺失的小鼠乳腺上皮细胞能够在纤维胶原等刚性基质上黏附和存活。t-ASPP2 诱导的肌动球蛋白松弛依赖于其与蛋白磷酸酶 1 的相互作用，但不依赖于 t-ASPP2 诱导的 YAP 激活。截断的 ASPP2 通过 E-钙黏蛋白缺失和 PI3K 通路的激活（通过 PTEN 缺失）与 ILC 的发展协同作用。t-ASPP2 诱导的肌动球蛋白松弛对于 ILC 的起始是必需的，但对于进展不是必需的。相反，t-ASPP2 诱导的 YAP 激活有助于肿瘤的生长和进展，而对肿瘤的起始是可有可无的。综上所述，这些发现强调了 t-ASPP2 通过两种不同的机制促进 ILC 起始和进展。意义：截断的 ASPP2 与 E-钙黏蛋白和 PTEN 的缺失协同作用，通过两种不同的机制驱动乳腺癌的起始和进展。ASPP2 诱导的肌动球蛋白松弛驱动肿瘤的起始，而 ASPP2 介导的 YAP 激活增强肿瘤的进展。
