Surmacz E
Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Mammary Gland Biol Neoplasia. 2000 Jan;5(1):95-105. doi: 10.1023/a:1009523501499.
The insulin-like growth factor-I receptor (IGF-IR) is a transmembrane tyrosine kinase regulating various biological processes such as proliferation, survival, transformation, differentiation, cell-cell and cell-substrate interactions. Different signaling pathways may underlie these pleiotropic effects. The specific pathways engaged depend on the number of activated IGF-IRs, availability of intracellular signal transducers, the action of negative regulators, and is influenced by extracellular modulators. Experimental and clinical data implicate the IGF-IR in breast cancer etiology. There is strong evidence linking hyperactivation of the IGF-IR with the early stages of breast cancer. In primary breast tumors, the IGF-IR is overexpressed and hyperphosphorylated, which correlates with radio-resistance and tumor recurrence. In vitro, the IGF-IR is often required for mitogenesis and transformation, and its overexpression or activation counteract effects of various pro-apoptotic treatments. In hormone-responsive breast cancer cells, IGF-IR function is strongly linked with estrogen receptor (ER) action. The IGF-IR and the ER are co-expressed in breast tumors. Moreover, estrogens stimulate the expression of the IGF-IR and its major signaling substrate IRS-1, while antiestrogens downregulate IGF-IR signaling, mainly by decreasing IRS-1 expression and function. On the other hand, overexpression of IRS-1 promotes estrogen-independence for growth and transformation. In ER-negative breast cancer cells, usually displaying a more aggressive phenotype, the levels of the IGF-IR and IRS-1 are often low and IGF is not mitogenic, yet the IGF-IR is still required for metastatic spread. Consequently, IGF-IR function in the late stages of breast cancer remains one of the most important questions to be addressed before rational anti-IGF-IR therapies are developed.
胰岛素样生长因子-I受体（IGF-IR）是一种跨膜酪氨酸激酶，可调节多种生物学过程，如增殖、存活、转化、分化、细胞间和细胞与底物的相互作用。不同的信号通路可能是这些多效性作用的基础。所涉及的特定通路取决于活化的IGF-IR的数量、细胞内信号转导分子的可用性、负调节因子的作用，并受细胞外调节剂的影响。实验和临床数据表明IGF-IR与乳腺癌病因有关。有强有力的证据将IGF-IR的过度激活与乳腺癌的早期阶段联系起来。在原发性乳腺肿瘤中，IGF-IR过度表达且过度磷酸化，这与放射抗性和肿瘤复发相关。在体外，有丝分裂和转化通常需要IGF-IR，其过度表达或激活可抵消各种促凋亡治疗的效果。在激素反应性乳腺癌细胞中，IGF-IR的功能与雌激素受体（ER）的作用密切相关。IGF-IR和ER在乳腺肿瘤中共同表达。此外，雌激素刺激IGF-IR及其主要信号底物IRS-1的表达，而抗雌激素主要通过降低IRS-1的表达和功能来下调IGF-IR信号传导。另一方面，IRS-1的过度表达促进生长和转化的雌激素非依赖性。在通常表现出更具侵袭性表型的ER阴性乳腺癌细胞中，IGF-IR和IRS-1的水平通常较低，IGF不具有促有丝分裂作用，但转移扩散仍需要IGF-IR。因此，在开发合理的抗IGF-IR疗法之前，IGF-IR在乳腺癌晚期的功能仍然是最重要的待解决问题之一。
