p53 in breast cancer subtypes and new insights into response to chemotherapy
p53 in breast cancer subtypes and new insights into response to chemotherapy
复制标题
DOI：
10.1016/j.breast.2013.07.005
复制
发表时间：
2013-08-01
期刊：
影响因子：
3.9
通讯作者：
de The, Hugues
中科院分区：
文献类型：
--
作者：
Bertheau, Philippe;Lehmann-Che, Jacqueline;de The, Hugues
尽管p53在癌症的特征中起着明显的核心作用，但TP53状态尚未用于乳腺癌的治疗。最近的发现可能会导致重新考虑P53在乳腺癌中的作用。TP53突变是乳腺癌中最常见的基因变化，在30%的乳腺癌中观察到。它们的分布与分子肿瘤亚型高度相关，在26%的腔[瘤]肿瘤(腔A占17%，腔B占41%)，在50%的HER2扩增的肿瘤中，在69%的分子顶分泌型乳腺癌和88%的基底细胞样癌中发现。突变类型与腔肿瘤中碱基对替换频率较高的肿瘤亚型有关，而分子顶分泌型和基底样瘤出现复杂突变(缺失/插入)的频率要高得多。TP53基因突变的时间也取决于肿瘤亚型，在腔性肿瘤中是第一个重要事件，但在基底细胞样瘤中发生在PTEN缺失之后。就细胞毒性化疗的反应而言，这种情况与随后的临床反应远不是P53依赖的细胞凋亡范例。我们报道了TP53突变的非炎症性局部晚期乳腺癌对剂量密集的阿霉素环磷酰胺化疗有很高的病理完全缓解率，而TP53野生型(WT)肿瘤从未达到完全缓解率。使用人乳腺癌异种移植模型，我们认为这可能是由于诱导了TP53WT肿瘤细胞的衰老。最近的一项工作证实了在MMTV-WNTL乳腺肿瘤中的这些发现，表明在多柔比星治疗后，TP53 WT肿瘤诱导生长停滞和衰老表型，而不是凋亡，而在突变肿瘤中缺乏抑制导致异常有丝分裂、细胞死亡和更好的临床反应。此外，在ER阳性(ER(+))的乳腺肿瘤中，最近有报道ER抑制了DNA损伤诱导的P53介导的凋亡反应。综上所述，这些数据有助于更好地了解乳腺癌中以阿霉素为基础的化疗的P53介导的反应：在ER(+)TP53WT乳腺癌中，ER诱导的P53凋亡反应的抑制将优先导致肿瘤细胞衰老和随后的治疗抵抗。相反，在ER阴性(ER())TP53突变的乳腺癌中，基因异常的积累会导致有丝分裂灾难和随后更好的反应。鉴于这些最近的结果，应该重新考虑P53在乳腺癌中的影响。(C)2013爱思唯尔有限公司。保留所有权利。
Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer.TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of lumina] tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base-pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in lumina] tumors but occurring after PTEN loss in basal-like tumors.Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wntl mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment. Conversely, in ER negative (ER()) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response.In view of these recent results, p53 impact in breast cancer should be reconsidered. (C) 2013 Elsevier Ltd. All rights reserved.