Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β.
Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β.
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DOI：
10.1091/mbc.e12-10-0776
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发表时间：
2013-11
影响因子：
3.3
通讯作者：
Schiemann WP
中科院分区：
文献类型：
--
作者：
Parvani JG;Galliher-Beckley AJ;Schiemann BJ;Schiemann WP
β1整合素的化学靶向已经被提出作为减轻乳腺癌转移的一种方式。本文显示，β1整联蛋白的失活促进β3整联蛋白的代偿性表达，其挽救乳腺肿瘤生长和转移，以及促进晚期乳腺癌中的致癌性TGF-β信号传导。乳腺肿瘤发生和上皮-间质转化（EMT）程序合作将转化生长因子-β（TGF-β）从乳腺癌转移的抑制剂转化为促进剂。尽管先前的报道将β1和β3整合素与TGF-β刺激EMT和转移相关联，但这些粘附分子在形成TGF-β的致癌活性中表现出的功能相互作用和可塑性仍然未知。我们证明β1整合素的失活损害了TGF-β刺激正常和恶性乳腺上皮细胞（MEC）的运动性，并仅在恶性MEC中引起β3整合素的强代偿性表达，而在其正常对应物中则不。补偿性β3整联蛋白表达还1）增强恶性MEC在刚性和顺应性三维器官型培养物中的生长和2）恢复TGF-β对EMT表型的诱导。重要的是，β3整联蛋白的代偿性表达挽救了小鼠中β1整联蛋白缺陷型4 T1肿瘤的生长和肺转移，这一过程可通过β3整联蛋白的遗传耗竭或功能失活来阻止。总之，我们的研究结果表明，β1整合素的失活通过β3整合素特异性机制促进转移进展，表明β1和β3整合素双重靶向对于减轻乳腺癌患者的转移性疾病是必要的。
Chemotherapeutic targeting of β1 integrin has been proposed as a way to alleviate breast cancer metastasis. It is shown here that inactivation of β1 integrin elicits compensatory expression of β3 integrin, which rescues mammary tumor growth and metastasis, as well as promoting oncogenic TGF-β signaling in late-stage breast cancer. Mammary tumorigenesis and epithelial–mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin–deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin–specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.