Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Department of Academic Biochemistry, The Royal Marsden Hospital; and London Research Institute, Cancer Research UK, London, United Kingdom.
Cancer Res. 2013 Jun 15;73(12):3783-95. doi: 10.1158/0008-5472.CAN-12-4265. Epub 2013 May 6.
Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRα1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer.
大多数诊断出的乳腺癌为雌激素受体阳性（ER(+）），并且依赖雌激素生长和存活。因此，通过芳香酶抑制剂阻断雌激素生物合成已成为 ER(+)乳腺癌绝经后妇女的一线内分泌治疗方法。尽管为患者的预后提供了显著改善，但芳香酶抑制剂耐药仍然是一个主要的临床挑战。受体酪氨酸激酶 RET 及其辅助受体 GFRα1 在一部分 ER(+)乳腺癌中上调，而炎症细胞因子上调了 RET 配体胶质源性神经营养因子（GDNF）。在这里，我们报告了一项多学科策略的研究结果，该策略旨在解决 GDNF-RET 信号在芳香酶抑制剂治疗反应中的影响。在二维和三维培养的乳腺癌细胞中，在芳香酶抑制剂耐药模型中，GDNF 介导的 RET 信号增强。此外，GDNF-RET 信号促进了芳香酶抑制剂耐药细胞的存活，并引起了芳香酶抑制剂敏感细胞的耐药性。这两种作用都可以通过 RET 激酶抑制剂 NVP-BBT594 选择性逆转。在 ER(+)癌症中的基因表达谱确定了一种与增殖无关的 GDNF 反应特征，该特征预示着患者预后不良，更重要的是，预测了对芳香酶抑制剂治疗的不良反应，从而导致耐药性的发展。我们通过显示在独立的芳香酶抑制剂耐药患者标本中增加的 RET 蛋白表达水平验证了这些发现。总之，我们的结果确立了 GDNF-RET 信号作为一种合理的治疗靶点，以对抗或延迟乳腺癌中芳香酶抑制剂耐药的发生。
