Endocrine Oncology Research Group, Department of Surgery and Epidemiology, Royal College of Surgeons in Ireland, University College Dublin, Dublin, Ireland.
Clin Cancer Res. 2012 Jun 15;18(12):3305-15. doi: 10.1158/1078-0432.CCR-11-3300. Epub 2012 May 1.
The use of aromatase inhibitors (AI) in the treatment of estrogen receptor (ER)-positive, postmenopausal breast cancer has proven efficacy. However, inappropriate activation of ER target genes has been implicated in the development of resistant tumors. The ER coactivator protein AIB1 has previously been associated with initiation of breast cancer and resistance to endocrine therapy.
Here, we investigated the role of AIB1 in the deregulation of ER target genes occurring as a consequence of AI resistance using tissue microarrays of patients with breast cancer and cell line models of resistance to the AI letrozole.
Expression of AIB1 associated with disease recurrence (P = 0.025) and reduced disease-free survival time (P = 0.0471) in patients treated with an AI as first-line therapy. In a cell line model of resistance to letrozole (LetR), we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole. In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole. Molecular studies revealed that this may be due in part to direct steroid regulation of c-jun-NH(2)-kinase (JNK), signaling to Jun and Fos at the cyclin D1 promoter.
This study establishes a role for AIB1 in AI-resistant breast cancer and describes a new mechanism of ERα/AIB1 gene regulation which could contribute to the development of an aggressive tumor phenotype.
芳香化酶抑制剂（AI）在治疗雌激素受体（ER）阳性、绝经后乳腺癌方面已被证实具有疗效。然而，ER 靶基因的不适当激活与耐药肿瘤的发生有关。ER 共激活蛋白 AIB1 先前与乳腺癌的发生和内分泌治疗的耐药性有关。
在这里，我们使用乳腺癌患者的组织微阵列和对 AI 来曲唑耐药的细胞系模型，研究了 AIB1 在 AI 耐药时 ER 靶基因失调中的作用。
在接受 AI 作为一线治疗的患者中，AIB1 的表达与疾病复发（P = 0.025）和无病生存时间缩短（P = 0.0471）相关。在来曲唑耐药的细胞系模型中，我们发现，即使存在雄烯二酮和来曲唑，ERα/AIB1 启动子的募集以及随后经典 ER 靶基因 pS2 和 Myc 的表达也持续上调。相比之下，ERα/AIB1 转录复合物向非经典 ER 靶基因 cyclin D1 的募集及其随后的表达仍然对类固醇处理敏感，并且可以通过来曲唑治疗抑制。分子研究表明，这部分可能是由于类固醇直接调节 c-jun-NH2-激酶（JNK），从而在 cyclin D1 启动子处向 Jun 和 Fos 发出信号。
本研究确立了 AIB1 在 AI 耐药性乳腺癌中的作用，并描述了一种新的 ERα/AIB1 基因调控机制，这可能有助于形成侵袭性肿瘤表型。
