Khan Zahid, Arafah Maha, Shaik Jilani Purusottapatnam, Mahale Alka, Alanazi Mohammad Saud
Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh.
Department of Pathology, College of Medicine, King Saud University, Riyadh.
Onco Targets Ther. 2018 Jan 11;11:323-335. doi: 10.2147/OTT.S154395. eCollection 2018.
Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients.
We immunohistochemically examined various components of Wnt signaling pathway including β-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women.
Cytoplasmic β-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of β-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic β-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers.
High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs targeting this pathway.
乳腺癌是全球女性中最常见的恶性肿瘤，也是癌症相关死亡的主要原因，在沙特阿拉伯也不例外。沙特女性乳腺癌发病年龄较早，中位发病年龄为49岁，而美国患者的中位发病年龄为62岁。无翅型和整合位点生长因子（Wnt）信号通路异常在乳腺癌发生过程中具有病理意义，因此对其在沙特患者中的作用进行了研究。
我们采用免疫组织化学方法检测了Wnt信号通路的各种成分，包括β-连环蛋白、肿瘤抑制蛋白、腺瘤性息肉病基因（APC）和轴蛋白，以及天然存在的通路拮抗剂如Dickkopf Wnt信号通路抑制剂3（DKK3）、FRP2和WIF1的表达，同时检测了Wnt靶基因细胞周期蛋白D1和c-Myc的表达，以确定该通路在沙特女性乳腺癌中是否持续激活。
在24%的病例中观察到细胞质β-连环蛋白，这表明该通路被激活。β-连环蛋白破坏复合物的成分APC和轴蛋白的表达分别在5%和10%的肿瘤中缺失。此外，Wnt信号抑制剂DKK3、FRP2和Wnt抑制因子1（WIF1）分别在8%、14%和5%的乳腺肿瘤中未表达。总体而言，在我们的队列中，约一半（47%）的乳腺癌中发现了细胞质β-连环蛋白的积累和其他Wnt通路蛋白（APC/轴蛋白/DKK3/FRP2/WIF1）的下调。与此一致，对Wnt靶基因的分析表明，58%的乳腺癌中c-Myc呈中度至强表达，50%的乳腺癌中细胞周期蛋白D1呈中度至强表达。Wnt通路失调与疾病发病年龄、肿瘤分级和乳腺癌的三阴性状态无关。
Wnt通路蛋白的高度失调表达表明其在沙特女性乳腺癌发病机制中起重要作用，这些女性可能受益于针对该通路的治疗药物的开发。
