Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Breast Cancer Res. 2010;12(3):R40. doi: 10.1186/bcr2594. Epub 2010 Jun 22.
Accumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype.
We defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays.
Within ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines.
Our data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity.
越来越多的证据表明，雌激素受体（ER）和孕激素受体（PR）的水平和活性都受到生长因子受体（GFR）信号通路的显著影响，这种串扰是乳腺癌进展和对治疗反应的主要决定因素。磷脂酰肌醇 3-激酶（PI3K）通路是 GFR 信号的关键介质之一，是乳腺癌中改变最明显的通路之一。因此，我们研究了在腔ER+乳腺癌肿瘤中失调的 PI3K 信号是否与 ER 水平和活性以及内在分子亚型相关。
我们定义了 PI3K 通路的两个独立的分子特征：基于 PI3K 信号转导中间产物的蛋白质测量的蛋白质组学（反相蛋白质组阵列）PI3K 特征，以及基于 PI3K 抑制剂诱导或抑制的基因集的 PI3K 转录（mRNA）特征。使用这些特征，我们对多个独立表达谱数据集（4 个 mRNA，n=915；1 个蛋白质，n=429）中代表的每个 ER+乳腺癌肿瘤进行了 PI3K 通路激活评分。通过定量实时 PCR 和细胞增殖测定来测试 PI3K 抑制剂 BEZ-235 对 ER 表达和活性水平以及细胞生长的影响。
在 ER+肿瘤中，在所有检查的数据集上，ER 水平与蛋白质组学和转录水平的 PI3K 激活评分均呈负相关。PI3K 特征评分在更具侵袭性的腔 B 分子亚型的 ER+肿瘤和细胞系中也更高，而在侵袭性较低的腔 A 亚型中则较低。值得注意的是，在四种不同的 ER+细胞系中，BEZ-235 治疗增加了 ER 和 ER 靶基因（包括 PR）的表达，而 IGF-I（通过 PI3K 信号）的治疗降低了 ER 和靶基因的表达，从而进一步确立了 ER 和 PI3K 之间的反向功能关系。BEZ-235 对他莫昔芬在抑制多种 ER+细胞系生长方面也有额外作用。
我们的数据表明，腔 B 肿瘤具有与内分泌治疗耐药相关的过度活跃的 GFR/PI3K 信号，与较低的 ER 水平相关。针对这些肿瘤中的 PI3K 可能会逆转 ER 表达和信号的丧失，并恢复激素敏感性。
