Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression.
Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression.
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DOI：
10.1158/0008-5472.can-20-0278
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发表时间：
2020-12-01
期刊：
影响因子：
11.2
通讯作者：
Castillo-Lluva S
中科院分区：
文献类型：
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作者：
Blanco-Gómez A;Hontecillas-Prieto L;Corchado-Cobos R;García-Sancha N;Salvador N;Castellanos-Martín A;Sáez-Freire MDM;Mendiburu-Eliçabe M;Alonso-López D;De Las Rivas J;Lorente M;García-Casas A;Del Carmen S;Abad-Hernández MDM;Cruz-Hernández JJ;Rodríguez-Sánchez CA;Claros-Ampuero J;García-Cenador B;García-Criado J;Orimo A;Gridley T;Pérez-Losada J;Castillo-Lluva S
SNAI2的过度表达似乎与乳腺癌的预后不良有关，但目前还不清楚这种情况发生在哪些乳腺癌亚型中。在这里，我们发现SNAI2过多与腔性B HER2+乳腺癌的预后不良有关，在这种乳腺癌中，SNAI2在间质中的表达与肿瘤的增殖无关。为了确定间质SNAI2如何影响HER2+肿瘤行为，将SNAI2缺陷小鼠与携带ErbB2/Neu原癌基因的小鼠系杂交，产生HER2+乳腺癌。在这个模型中产生的肿瘤在间质中表达SNAI2，但不在上皮中表达，这使得可以在不受上皮间隔膜干扰的情况下研究间质SNAI2的作用。HER2/ERBB2+肿瘤间质中SNAI2的缺失与：(1)细胞周期蛋白D1水平降低，肿瘤上皮细胞增殖减少；(2)AKT水平升高，转移发生率降低；(3)血管生成素-2水平降低，肿瘤坏死增多有关。综上所述，这些结果表明，肿瘤相关成纤维细胞中SNAI2的缺失限制了某些细胞因子的产生，从而影响了AKT/ERK肿瘤信号转导和ERBB2+乳腺癌细胞随后的增殖和转移能力。因此，SNAI2在间质中的表达增强了管腔B ERBB2+乳腺癌的致瘤性。这项工作强调了间质SNAI2在乳腺癌进展和患者预后中的重要性。在管腔B-HER2阳性乳腺癌患者中，SNAI2在间质中的过度表达而不是在上皮中的过度表达与预后不良有关。
SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2/ERBB2+ tumors is associated with: (i) lower levels of CYCLIN D1 and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of ANGIOPOIETIN-2 and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. SNAI2 overexpression in the stroma and not in the epithelium is associated with a poor prognosis in luminal B-HER2+ breast cancer patients.