Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.
Clinicopathological and Functional Significance of RECQL1 Helicase in Sporadic Breast Cancers.
复制标题
RECQL1解旋酶在零星乳腺癌中的临床病理学和功能意义。
DOI：
10.1158/1535-7163.mct-16-0290
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发表时间：
2017-01
影响因子：
5.7
通讯作者：
Madhusudan S
中科院分区：
文献类型：
--
作者：
Arora A;Parvathaneni S;Aleskandarany MA;Agarwal D;Ali R;Abdel-Fatah T;Green AR;Ball GR;Rakha EA;Ellis IO;Sharma S;Madhusudan S
RECQL 1是DNA解旋酶RecQ家族的关键成员，是DNA复制和DNA修复所必需的。最近的两项研究表明，生殖系RECQL 1突变与乳腺癌易感性增加有关。RECQL 1表达的改变是否在散发性乳腺癌中具有临床病理学意义尚不清楚。我们在转录组水平[METABRIC队列，n=1977]和蛋白质水平[队列1，n=897;队列2，n= 252;队列3（BRCA-生殖细胞缺陷），n=74]评估了RECQL 1。在RECQL 1缺失的乳腺癌细胞中，我们研究了蒽环类药物的敏感性。高RECQL 1 mRNA与intClust.3相关（p=0.026），其特征在于低基因组不稳定性。另一方面，低RECQL 1 mRNA与intClust.8（管腔A ER+亚组）（p=0.0455）和intClust.9（管腔B ER+亚组）（p=0.0346）分子表型相关。RECQL 1低表达与乳腺癌特异性生存期较短相关（p=0.001）。在蛋白水平，低细胞核RECQL 1水平与较大的肿瘤大小、淋巴结阳性、高肿瘤分级、高有丝分裂指数、多形性、去分化、ER阴性和HER-2过表达相关（p值<0.05）。在接受内分泌治疗的ER+肿瘤中，低RECQL 1与生存率低相关（p=0.008）。然而，在接受蒽环类药物化疗的ER阴性肿瘤中，高RECQL 1与生存率低相关（p=0.048）。在RECQL 1缺失的乳腺癌细胞系中，我们证实了阿霉素的敏感性，这与DNA双链断裂积累、S期细胞周期阻滞和细胞凋亡有关。我们得出结论，RECQL 1在乳腺癌中具有预后和预测意义。
RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germ-line RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathological significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level [METABRIC cohort, n=1977] and at the protein level [cohort 1, n=897; cohort 2, n= 252; cohort 3 (BRCA-germline deficient), n=74]. In RECQL1-depleted breast cancer cells we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (p=0.026) which is characterised by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 (luminal A ER+ sub-group) (p=0.0455) and intClust.9 (luminal B ER+ sub-group) (p=0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer specific survival (p=0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumour size, lymph node positivity, high tumour grade , high mitotic index, pleomorphism, de-differentiation, ER negativity and HER-2 overexpression (p values<0.05). In ER+ tumours that received endocrine therapy, low RECQL1 was associated with poor survival (p=0.008). However, in ER− negative tumours that received anthracycline based chemotherapy, high RECQL1 was associated with poor survival (p=0.048). In RECQL1-depleted breast cancer cell lines we confirmed doxorubicin sensitivity which was associated with DNA double strand breaks accumulation, S-phase cell cycle arrest and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers.