Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways
Endocrine resistance associated with activated ErbB system in breast cancer cells is reversed by inhibiting MAPK or PI3K/Akt signaling pathways
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DOI：
10.1002/ijc.24750
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发表时间：
2010-01-15
影响因子：
6.4
通讯作者：
Cohen, Pascale A.
中科院分区：
文献类型：
--
作者：
Ghayad, Sandra E.;Vendrell, Julie A.;Cohen, Pascale A.
内分泌治疗抵抗是治疗雌激素受体阳性（ER+）乳腺癌患者的主要挑战之一。该研究表明，在OH-他莫昔芬选择下获得两种不同的内分泌抗性表型的MCF-7（MVLN细胞）衍生的两种ER+人乳腺癌细胞系均显示PI 3 K/Akt和MAR途径的组成性激活。在两种耐药细胞系中还观察到ErbB系统的异常表达和激活（磷酸化EGFR、磷酸化ErbB 2、磷酸化ErbB 3、ErbB 4的过表达和几种ErbB配体的过表达），这表明存在导致MAPK和PI 3 K/Akt存活通路的组成性激活的自分泌环。近年来，特异性信号转导抑制剂的临床应用是乳腺癌最有前途的治疗方法之一。MEK抑制剂PD 98059和PI 3 K抑制剂LY 294002都能够增强OH-他莫昔芬或氟维司群对MVLN敏感细胞的细胞抑制作用。在两种耐药细胞系中，与内分泌治疗相关的MAPK或PI 3 K/Akt通路的抑制足以逆转OH-他莫昔芬或氟维司群耐药。研究两种抑制剂联合使用对两种耐药细胞系中OH-他莫昔芬和氟维司群耐药性逆转的影响表明，在临床实践中，联合使用两种抑制剂的策略将是针对不同内分泌耐药的最佳方法可能存在于肿瘤中。总之，MAPK和PI 3 K抑制剂的组合代表了克服ER+乳腺癌患者中的内分泌治疗抗性的有希望的策略。
Endocrine therapy resistance is one of the main challenges in the treatment of estrogen receptor positive (ER+) breast cancer patients. This study showed that two ER+ human breast carcinoma cell lines derived from MCF-7 (MVLN cells) that have acquired under OH-Tamoxifen selection two distinct phenotypes of endocrine resistance both displayed constitutive activation of the PI3K/Akt and MAR pathways. Aberrant expression and activation of the ErbB system (phospho-EGFR, phospho-ErbB2, phospho-ErbB3, over-expression of ErbB4 and over-expression of several ErbB ligands) were also observed in the two resistant cell lines, suggesting the existence of an autocrine loop leading to constitutive activation of MAPK and PI3K/Akt survival pathways. The recent clinical use of specific signal transduction inhibitors is one of the most promising therapeutic approaches in breast cancers. The MEK inhibitor PD98059 and the PI3K inhibitor LY294002 were both able to enhance the cytostatic effect of OH-Tamoxifen or fulvestrant on MVLN sensitive cells. In the two resistant cell lines, inhibition of the MAPK or the PI3K/Akt pathways associated with endocrine therapy was sufficient to reverse OH-Tamoxifen or fulvestrant resistance. Investigating the effect of a combination of both inhibitors on the reversion of OH-Tamoxifen and fulvestrant resistance in the two resistant cell lines suggested that, in clinical practice, a strategy combining the two inhibitors would be the best approach to target the different endocrine resistance phenotypes possibly present in a tumor. In conclusion, the combination of MAPK and PI3K inhibitors represents a promising strategy to overcome endocrine therapy resistance in ER+ breast cancer patients.