Arteaga C L, Osborne C K
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7884.
Cancer Res. 1989 Nov 15;49(22):6237-41.
Insulin and insulin-like growth factors (IGFs) stimulate the growth of human breast cancer cells in vitro. The type I somatomedin receptor (SR), expressed in these cells, may mediate the mitogenic effects of these peptides. We have examined the effect of type I SR blockade on human breast cancer growth with a monoclonal antibody (alpha-IR3) that blocks the receptor binding domain. alpha-IR3 inhibited binding of 125I-IGF-I in all breast cancer cell lines tested. Binding affinity of alpha-IR3 was 2 to 5 times higher than that of IGF-I in MDA-231 (Kd 2.1 nM) and MCF-7 cells (Kd 0.6 nM), respectively. In the presence of 10% calf serum, the antibody inhibited anchorage-independent growth of six of seven breast cancer cell lines. This inhibition was reversible with excess IGF-I. In serum-free medium, alpha-IR3 blocked IGF-I-stimulated DNA synthesis in four of four breast cancer cell lines (MCF-7, ZR75-1, MDA-231, and HS578T). However, the antibody did not inhibit basal growth of any of the breast cancer cell lines in serum-free conditions. In three estrogen receptor-positive, estrogen-responsive breast cancer cell lines (MCF-7, ZR75-1, and T47D), type I SR blockade with alpha-IR3 failed to block estrogen-stimulated DNA synthesis or cell proliferation, indicating that secreted IGF activity is not the sole mediator of the growth effects of estrogen. In conclusion, antibody-mediated type I SR blockade does not inhibit basal growth of breast cancer cells under serum-free conditions, arguing against a critical autocrine role of endogenously secreted IGF activity in vitro. However, type I SR blockade inhibits breast cancer cell growth in the presence of serum, suggesting that serum IGFs might be critical endocrine or paracrine regulators of human breast cancer.
胰岛素及胰岛素样生长因子（IGFs）在体外可刺激人乳腺癌细胞生长。这些细胞中表达的Ⅰ型生长调节素受体（SR）可能介导了这些肽的促有丝分裂作用。我们用一种能阻断受体结合域的单克隆抗体（α-IR3）研究了Ⅰ型SR阻断对人乳腺癌生长的影响。α-IR3抑制了所有测试的乳腺癌细胞系中125I-IGF-I的结合。在MDA-231细胞（解离常数Kd为2.1 nM）和MCF-7细胞（Kd为0.6 nM）中，α-IR3的结合亲和力分别比IGF-I高2至5倍。在含有10%小牛血清的情况下，该抗体抑制了7个乳腺癌细胞系中6个的非锚定依赖性生长。这种抑制作用可被过量的IGF-I逆转。在无血清培养基中，α-IR3阻断了4个乳腺癌细胞系（MCF-7、ZR75-1、MDA-231和HS578T）中IGF-I刺激的DNA合成。然而，该抗体在无血清条件下并未抑制任何乳腺癌细胞系的基础生长。在3个雌激素受体阳性且对雌激素有反应的乳腺癌细胞系（MCF-7、ZR75-1和T47D）中，用α-IR3阻断Ⅰ型SR未能阻断雌激素刺激的DNA合成或细胞增殖，这表明分泌的IGF活性并非雌激素生长效应的唯一介导因素。总之，抗体介导的Ⅰ型SR阻断在无血清条件下并不抑制乳腺癌细胞的基础生长，这表明内源性分泌的IGF活性在体外并非关键的自分泌作用。然而，Ⅰ型SR阻断在有血清存在时可抑制乳腺癌细胞生长，这表明血清IGFs可能是人类乳腺癌关键的内分泌或旁分泌调节因子。
