乳腺癌他莫昔芬耐药过程中HOXB7调控ERα及HER2信号网络的机制研究

Estrogen signaling plays a pivotal role in breast cancer development. Endocrine therapy including tamoxifen treatment to block the ER pathway is highly effective and can significantly promote survival in ER positive breast cancer patients, but its clinical application was limited by drug resistance. We have recently demonstrated that HOXB7, a homeobox protein, was overexpressed in breast cancer cells to result in tamoxifen resistance via its direct interaction with EGFR pathway. In the present study, we find that HOXB7 activated ERα responsive genes in a ligand independent manner. We also find that HER2 mRNA level was markedly increased in cells with forced expression of HOXB7. Bioinformatics analysis indicates that the potential responsive genes of HOXB7 and ERα are significantly overlapped, suggesting their functional linkage. We further identified HOXB7 as potential miR-653 regulated target gene in tamoxifen resistant cells. We will further investigate the molecular network involving miR-653 and HOXB7 regulated ERα and HER2 signaling. It is with hope that the proposed studies should improve our understanding of ER+ breast cancer therapeutics and might be helpful to circumvent tamoxifen resistance with renewed efforts.

雌激素在雌激素受体阳性（ER+）乳腺癌的发生发展中起着关键性的作用，以雌激素拮抗剂他莫昔芬（TAM）为代表的内分泌疗法通过阻断ER信号通路可以显著提高ER+患者的生存率。然而长期服用TAM所带来的治疗耐受一直困扰着临床实践。我们前期的研究发现同源异型基因HOXB7在TAM长期诱导的抗性细胞中表达上调并通过直接激活EGFR通路介导细胞的药物耐受。本项目前期，我们进一步发现HOXB7可以引发雌激素应答基因非配体依赖性转录上调，同时伴随着HER2 mRNA的表达上升；生物信息学分析显示HOXB7和ERα的潜在转录应答基因之间存在明显的重叠，我们设想它们可能在功能上连锁。我们还发现miR-653在耐药细胞中表达下调并直接调控HOXB7的表达。本课题将深入研究miR-653与HOXB7调控ERα及HER2的相关分子网络，从而为进一步提高ER+乳腺癌的治疗与预后水平，为克服临床治疗抗药性提供新的策略。

受本项目资金的支持，项目执行的过去3年按照既定目标就HOXB7调控ER+乳腺癌细胞的内分泌耐药以及肿瘤治疗相关靶标的分子机制与干预手段等方面开展了系统深入的研究，取得了一系列的研究成果，超额完成了既定的目标与任务。主要代表性的工作包括发现HOXB7作为ERα的辅助因子调控HER2的激活导致内分泌耐药, 发现人生长激素和人催乳素通过自分泌和旁分泌的方式促进肝细胞癌的发展与潜在的干预手段。揭示数个miRNA, Artemin以及TFF3作为乳腺癌等肿瘤治疗的潜在靶标的作用机制,取得了一系列的科研成果。受本基金支持，我们共发表Journal of Biological Chemistry、Oncotarget、PLoS One等国际期刊发表SCI学术论文4篇，其中第一作者论文一篇发表在Oncotarget上。本项目的圆满完成为未来深入的研究肿瘤相关治疗策略奠定了良好的基础。