Department of Pathology, Hospital Saint-Louis, APHP, University Paris Diderot, INSERM U728, Paris, France.
Breast. 2013 Aug;22 Suppl 2:S27-9. doi: 10.1016/j.breast.2013.07.005.
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 luminal 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 luminal 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-Wnt1 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.
尽管 p53 在癌症的标志性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管理。最近的发现可能会促使人们重新考虑 p53 在乳腺癌中的作用。TP53 突变是乳腺癌中最常见的遗传改变，在 30%的乳腺癌中观察到。它们的分布与 26%的腔隙肿瘤中发现的分子肿瘤亚型高度相关（腔隙 A 中的 17%，腔隙 B 中的 41%），在 50%的 HER2 扩增肿瘤中，在 69%的分子大汗腺癌中，在 88%的基底样癌中。突变类型与肿瘤亚型相关，腔隙肿瘤中碱基对替换的频率更高，而分子大汗腺癌和基底样癌的复杂突变（缺失/插入）频率更高。TP53 突变的时间也取决于肿瘤亚型，在腔隙肿瘤中是第一个重要事件，但在基底样肿瘤中是在 PTEN 丢失之后。关于细胞毒性化疗的反应，情况远非依赖于 p53 的凋亡范例，随后是临床反应。我们报告说，TP53 突变的非炎症局部晚期乳腺癌对密集剂量多柔比星-环磷酰胺化疗有很高的完全病理缓解率，而 TP53 野生型（WT）肿瘤从未达到完全缓解。使用人乳腺癌异种移植模型，我们认为这可能是由于 TP53 WT 肿瘤细胞中诱导了衰老。最近的一项工作在 MMTV-Wnt1 乳腺肿瘤中证实了这些发现，表明多柔比星治疗后，TP53 WT 肿瘤中诱导了生长停滞和衰老表型，而不是凋亡，而突变肿瘤中缺乏阻滞导致异常有丝分裂、细胞死亡和更好的临床反应。此外，在雌激素受体阳性（ER(+)）乳腺癌中，最近有报道称，雌激素受体抑制 DNA 损伤诱导的 p53 介导的凋亡反应。综上所述，这些数据可以帮助更好地理解乳腺癌中基于多柔比星的化疗中 p53 介导的反应：在 ER(+)TP53 WT 乳腺癌中，雌激素受体诱导的 p53 凋亡反应抑制将优先导致肿瘤细胞衰老和随后的治疗耐药。相反，在雌激素受体阴性（ER(-））TP53 突变的乳腺癌中，遗传异常的积累将导致有丝分裂灾难，随后反应更好。鉴于这些最近的结果，p53 对乳腺癌的影响应该重新考虑。
