The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.
The gain of function of p53 cancer mutant in promoting mammary tumorigenesis.
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DOI：
10.1038/onc.2012.299
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Xu, Y.
中科院分区：
文献类型：
--
作者：
Lu, X.;Liu, D. P.;Xu, Y.
肿瘤抑制因子p53对抑制包括乳腺癌在内的所有类型的人类癌症至关重要。在一半以上的人类癌症中，p53基因发生了体细胞突变。大多数p53突变是错义突变，导致全长p53突变体的表达。包括R175H在内的几个热点突变在人类乳腺癌中经常被检测到。P53癌突变体不仅失去了抑瘤活性，更令人担忧的是，它还获得了新的致癌活性。尽管p53癌突变体的表达与人类乳腺癌患者预后不良相关，但p53癌突变体在促进乳腺癌中的作用尚不清楚。我们利用人源化p53癌突变敲入（R175H）小鼠和MMTV-Wnt-1转基因（mWnt-1）小鼠特异性研究R175H在促进乳腺癌中的功能获得。虽然R175H/R175HmWnt-1（R175HmWnt-1）和p53 - / - mWnt-1小鼠死于乳腺癌的动力学相同，比mWnt-1小鼠早得多，但R175HmWnt-1小鼠每只小鼠大多出现多个乳腺肿瘤，而p53 - / - mWnt-1和mWnt-1小鼠每只小鼠大多出现一个肿瘤。在同一只R175HmWnt-1小鼠中出现的多发乳腺肿瘤表现出不同的组织学特征。此外，R175H功能获得突变体扩展了导致乳腺肿瘤的乳腺上皮干细胞（MESCs）。由于ATM抑制MESCs的扩增，因此R175H对乳腺上皮细胞中ATM的失活可能有助于R175HmWnt-1小鼠MESCs的扩增。这些发现为R175H通过扩大MESCs促进乳腺癌的发生提供了基础。
Tumor suppressor p53 is critical to suppress all types of human cancers, including breast cancers. The p53 gene is somatically mutated in over half of all human cancers. The majority of the p53 mutations are missense mutations, leading to the expression of the full-length p53 mutants. Several hotspot mutations, including R175H, are frequently detected in human breast cancers. P53 cancer mutants not only lose tumor suppression activity, but more problematically, gain new oncogenic activities. Despite correlation of the expression of p53 cancer mutants and the poor prognosis of human breast cancer patients, the roles of p53 cancer mutants in promoting breast cancer remain unclear. We employed the humanized p53 cancer mutant knock-in (R175H) mice and MMTV-Wnt-1 transgenic (mWnt-1) mice to specifically address the gain of function of R175H in promoting breast cancer. While both R175H/R175HmWnt-1(R175HmWnt-1) and p53−/−mWnt-1 mice died from mammary cancers at the same kinetics, which was much earlier than mWnt-1 mice, most of the R175HmWnt-1 mice developed multiple mammary tumors per mouse, whereas p53−/−mWnt-1 and mWnt-1 mice mostly developed one tumor per mouse. The multiple mammary tumors arose in the same R175HmWnt-1 mouse exhibited different histological characters. Moreover, R175H gain-of-function mutant expands the mammary epithelial stem cells (MESCs) that give rise to the mammary tumors. Since ATM suppresses the expansion of MESCs, the inactivation of ATM by R175H in mammary epithelial cells could contribute to the expansion of MESCs in R175HmWnt-1 mice. These findings provide the basis for R175H to promote the initiation of breast cancer by expanding MESCs.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.1073/pnas.88.11.5006
发表时间：
1991-06-01
影响因子：
11.1
作者：
DAVIDOFF, AM;HUMPHREY, PA;MARKS, JR
通讯作者：
MARKS, JR
影响因子：
254.7
作者：
Jemal, A;Tiwari, RC;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
64.8
作者：
Asselin-Labat, Marie-Liesse;Vaillant, Francois;Visvader, Jane E.
通讯作者：
Visvader, Jane E.
影响因子：
30.8
作者：
DITTMER, D;PATI, S;LEVINE, AJ
通讯作者：
LEVINE, AJ