Yousef Einas M, Furrer Daniela, Laperriere David L, Tahir Muhammad R, Mader Sylvie, Diorio Caroline, Gaboury Louis A
Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.
Department of Histology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
Mod Pathol. 2017 May;30(5):682-697. doi: 10.1038/modpathol.2016.231. Epub 2017 Jan 13.
Breast cancer is a heterogeneous disease comprising a diversity of tumor subtypes that manifest themselves in a wide variety of clinical, pathological, and molecular features. One important subset, luminal breast cancers, comprises two clinically distinct subtypes luminal A and B each of them endowed with its own genetic program of differentiation and proliferation. Luminal breast cancers were operationally defined as follows: Luminal A: ER+, PR+, HER2-, Ki-67<14% and Luminal B: ER+ and/or PR+, HER2-,Ki-67≥14% or, alternatively ER+ and/or PR+, HER2+, any Ki-67. There is currently a need for a clinically robust and validated immunohistochemical assay that can help distinguish between luminal A and B breast cancer. MCM2 is a family member of the minichromosome maintenance protein complex whose role in DNA replication and cell proliferation is firmly established. As MCM2 appears to be an attractive alternative to Ki-67, we sought to study the expression of MCM2 and Ki-67 in different histological grades and molecular subtypes of breast cancer focusing primarily on ER-positive tumors. MCM2 and Ki-67 mRNA expression were studied using in silico analysis of available DNA microarray and RNA-sequencing data of human breast cancer. We next used immunohistochemistry to evaluate protein expression of MCM2 and Ki-67 on tissue microarrays of invasive breast carcinoma. We found that MCM2 and Ki-67 are highly expressed in breast tumors of high histological grades, comprising clinically aggressive tumors such as triple-negative, HER2-positive and luminal B subtypes. MCM2 expression was detected at higher levels than that of Ki-67 in normal breast tissues and in breast cancers. The bimodal distribution of MCM2 scores in ER+/HER2- breast tumors led to the identification of two distinct subgroups with different relapse-free survival rates. In conclusion, MCM2 expression can help sorting out two clinically important subsets of luminal breast cancer whose treatment and clinical outcomes are likely to diverge.
乳腺癌是一种异质性疾病，由多种肿瘤亚型组成，这些亚型在临床、病理和分子特征方面表现出广泛的差异。一个重要的子集是管腔型乳腺癌，它包括临床上不同的两种亚型，即管腔A型和B型，每种亚型都有其自身的分化和增殖遗传程序。管腔型乳腺癌在操作上的定义如下：管腔A型：雌激素受体（ER）阳性、孕激素受体（PR）阳性、人表皮生长因子受体2（HER2）阴性、Ki-67<14%；管腔B型：ER阳性和/或PR阳性、HER2阴性、Ki-67≥14%，或者ER阳性和/或PR阳性、HER2阳性、任何Ki-67值。目前需要一种临床稳健且经过验证的免疫组织化学检测方法，以帮助区分管腔A型和B型乳腺癌。微小染色体维持蛋白2（MCM2）是微小染色体维持蛋白复合体的家族成员，其在DNA复制和细胞增殖中的作用已得到明确证实。由于MCM2似乎是Ki-67的一个有吸引力的替代指标，我们试图研究MCM2和Ki-67在不同组织学分级和分子亚型的乳腺癌中的表达，主要关注ER阳性肿瘤。我们利用对人类乳腺癌现有DNA微阵列和RNA测序数据的计算机分析来研究MCM2和Ki-67的mRNA表达。接下来，我们使用免疫组织化学方法评估MCM2和Ki-67在浸润性乳腺癌组织微阵列上的蛋白表达。我们发现，MCM2和Ki-67在高组织学分级的乳腺肿瘤中高表达，这些肿瘤包括临床上侵袭性较强的肿瘤，如三阴性、HER2阳性和管腔B型亚型。在正常乳腺组织和乳腺癌中，MCM2的表达水平高于Ki-67。ER+/HER2-乳腺肿瘤中MCM2评分的双峰分布导致识别出两个无复发生存率不同的不同亚组。总之，MCM2的表达有助于区分管腔型乳腺癌的两个临床上重要的亚组，其治疗和临床结果可能不同。
