The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Ann Oncol. 2013 Jan;24(1):126-33. doi: 10.1093/annonc/mds240. Epub 2012 Aug 2.
We have found that the platelet-derived growth factor receptor (PDGFR)/Abl signaling pathway is up-regulated as a determinant of the acquisition of resistance to estrogen deprivation in vitro. We aimed to determine its clinical relevance in aromatase inhibitor (AI)-resistant breast cancer.
We identified a cohort of 45 patients with estrogen receptor-positive breast cancer who had been treated with an AI, subsequently relapsed and had biopsy material available from both the presentation and post-AI recurrent lesion. PDGFRα, PDGFRβ and Abl expression was assessed in formalin-fixed paraffin-embedded sections.
Tumor protein expression of PDGFRα (1.39-fold, P=0.0065), PDGFRβ (4.32-fold, P=0.006) and Abl (1.8-fold, P=0.001) was increased at the point of relapse. Tumor and stromal expression of PDGFRα as well as PDGFRβ was significantly correlated in pre-treatment and relapse samples. High post-treatment tumor and stromal PDGFRβ levels were associated with a short time to treatment failure (TTF). Expression of PDGFRα in relapsing tumor specimens was correlated with Abl expression and Ki67 levels. Furthermore, changes in Abl correlated significantly with changes in ER expression.
These clinical data support a role for enhanced PDGF/Abl signaling in AI-resistant disease and provide a rationale for targeting the pathway in endocrine-resistant breast cancer.
我们发现血小板衍生生长因子受体（PDGFR）/Abl 信号通路的上调是体外获得雌激素剥夺耐药性的决定因素。我们旨在确定其在芳香酶抑制剂（AI）耐药性乳腺癌中的临床相关性。
我们鉴定了 45 名接受 AI 治疗的雌激素受体阳性乳腺癌患者的队列，这些患者随后复发，并且在 AI 复发病变的呈现和后有活检材料可用。评估了福尔马林固定石蜡包埋切片中的 PDGFRα、PDGFRβ 和 Abl 表达。
复发时肿瘤蛋白表达的 PDGFRα（1.39 倍，P=0.0065）、PDGFRβ（4.32 倍，P=0.006）和 Abl（1.8 倍，P=0.001）增加。治疗前和复发样本中肿瘤和基质的 PDGFRα 表达与 PDGFRβ 表达显著相关。高治疗后肿瘤和基质 PDGFRβ 水平与治疗失败时间（TTF）短相关。复发肿瘤标本中 PDGFRα 的表达与 Abl 表达和 Ki67 水平相关。此外，Abl 的变化与 ER 表达的变化显著相关。
这些临床数据支持增强的 PDGF/Abl 信号在 AI 耐药性疾病中的作用，并为靶向内分泌耐药性乳腺癌中的该途径提供了依据。
