Dunn S E, Ehrlich M, Sharp N J, Reiss K, Solomon G, Hawkins R, Baserga R, Barrett J C
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 1998 Aug 1;58(15):3353-61.
The 5-year survival rate for women with metastatic breast cancer is only 25-30%; thus, the need to improve treatment is apparent. Overexpression of insulin-like growth factor-I receptor (IGF-IR) correlates with poor prognosis and local recurrence. In this study, we addressed whether functional impairment of IGF-IR affects adhesion, invasion, and metastasis of breast cancer. Impairment of IGF-IR function was achieved by transfecting a dominant negative form of the receptor, termed 486stop, into MDA-MB-435 metastatic breast cancer cells. The protein product of 486stop is secreted extracellularly, resulting in a bystander effect. Cellular adhesion to laminin and collagen was inhibited 94 and 88%, respectively. Furthermore, 486stop inhibited insulin-like growth factor-I-stimulated invasion through collagen IV by 75%. The dominant negative receptor was secreted, as evidenced by the observation that MDA-MB-435 and MDA-MB-231 cells were prevented from binding to laminin by 90% when treated with conditioned medium (CM) from 486stop-transfected cells. CM also inhibited the invasion of MDA-MB-231 cells across collagen IV by 80%. Finally, CM made MDA-MB-231 cells 30% more sensitive to Taxol-induced cell death. Growth in soft agar was suppressed by 486stop, but growth in monolayer was unaffected. When injected into the mammary fat pad, 486stop did not significantly suppress growth of the primary tumor, but metastasis to the lungs, livers, lymph nodes, and lymph vessels was significantly decreased compared to the vector control. In conclusion, inhibition of IGF-IR resulted in suppression of adhesion, invasion, and metastasis, providing a mechanistic rationale for targeting IGF-IR in the treatment of metastatic breast cancer.
转移性乳腺癌女性的5年生存率仅为25% - 30%；因此，改善治疗的必要性显而易见。胰岛素样生长因子-I受体（IGF-IR）的过表达与预后不良和局部复发相关。在本研究中，我们探讨了IGF-IR的功能损伤是否会影响乳腺癌的黏附、侵袭和转移。通过将一种称为486stop的受体显性负性形式转染到MDA-MB-435转移性乳腺癌细胞中，实现了IGF-IR功能的损伤。486stop的蛋白质产物分泌到细胞外，产生旁分泌效应。细胞对层粘连蛋白和胶原蛋白的黏附分别被抑制了94%和88%。此外，486stop将胰岛素样生长因子-I刺激的通过IV型胶原蛋白的侵袭抑制了75%。显性负性受体被分泌出来，这一点可通过以下观察得到证明：当用来自转染了486stop的细胞的条件培养基（CM）处理时，MDA-MB-435和MDA-MB-231细胞与层粘连蛋白的结合被阻止了90%。CM还将MDA-MB-231细胞穿过IV型胶原蛋白的侵袭抑制了80%。最后，CM使MDA-MB-231细胞对紫杉醇诱导的细胞死亡的敏感性提高了30%。486stop抑制了软琼脂中的生长，但单层生长不受影响。当注射到乳腺脂肪垫中时，486stop并没有显著抑制原发性肿瘤的生长，但与载体对照相比，肺、肝、淋巴结和淋巴管的转移明显减少。总之，抑制IGF-IR导致黏附、侵袭和转移受到抑制，为在转移性乳腺癌治疗中靶向IGF-IR提供了机制依据。
