中美发现三阴性乳腺癌的候选药物
三阴性乳腺癌的雌激素受体、孕激素受体、人表皮生长因子受体2（HER2）三个主要治疗靶点均为阴性，占所有乳腺癌的12%～17%，其预后差、耐药性强、复发率和远处转移率高、生存率低、治疗手段少。
2019年1月14日，美国《细胞》旗下《癌细胞》将正式发表美国普林斯顿大学分子生物学系和新泽西州立罗格斯大学癌症研究所康毅滨、复旦大学附属肿瘤医院江一舟、刘依熔、邵志敏等学者的研究报告，发现一种体内天然分泌蛋白的重组药物可显著抑制乳腺癌原发肿瘤生长和自发转移，能同时阻断乳腺癌细胞繁殖并向其他器官扩散，有望成为治疗三阴性乳腺癌的候选药物。
肾小管间质性肾炎抗原样蛋白（Tinagl1）属于体内天然分泌蛋白之一，由TINAGL1基因编码，将其内源性异位表达，或将其重组药物治疗性注射，通过直接结合整联蛋白（整合素）α5β1、αvβ1和表皮生长因子受体（EGFR）随后同时抑制黏着斑激酶（FAK）和EGFR信号转导通路，7周后显著抑制了三阴性乳腺癌的生长和转移，癌细胞生长显著减缓，肺转移比例显著减少，即使发生转移，该药仍然可以抑制肿瘤生长，且未见明显副作用。此外，该研究通过对复旦大学附属肿瘤医院839例乳腺肿瘤标本的分析，发现Tinagl1表达水平与三阴性乳腺癌患者良好预后相关，并且与FAK和EGFR激活状态呈负相关。
因此，该研究结果表明，Tinagl1通过对整联蛋白→FAK和EGFR信号转导通路的双重抑制，有望成为三阴性乳腺癌的良好预后标志和候选治疗药物。
Cancer Cell. 2019 Jan 3. [Epub ahead of print]
Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling.
Minhong Shen, Yi-Zhou Jiang, Yong Wei, Brian Ell, Xinlei Sheng, Mark Esposito, Jooeun Kang, Xiang Hang, Hanqiu Zheng, Michelle Rowicki, Lanjing Zhang, Weichung J. Shih, Toni Celià-Terrassa, Yirong Liu, IIeana Cristea, Zhi-Ming Shao, Yibin Kang.
Princeton University, Princeton, NJ, USA; Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China; University Medical Center of Princeton, Plainsboro, NJ, USA; The State University of New Jersey, Piscataway, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
HIGHLIGHTS
Endogenous and recombinant Tinagl1 suppress growth and metastasis of breast cancer
Tinagl1 inhibits EGFR and integrin/FAK activation through distinct mechanisms
Tinagl1 level negatively correlates with EGFR and FAK activation in TNBC
Tinagl1 is a good prognosis marker and candidate therapeutic agent for TNBC
Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5β1, αvβ1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.
KEYWORDS: triple-negative breast cancer; Tinagl1; tumor-stromal interaction; extracellular matrix; integrin; EGFR; metastasis; FAK
DOI: 10.1016/j.ccell.2018.11.016
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