Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression.
Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression.
复制标题
DOI：
10.1242/dmm.008995
复制
发表时间：
2012-11
影响因子：
4.3
通讯作者：
Borowsky AD
中科院分区：
文献类型：
--
作者：
Vinall RL;Chen JQ;Hubbard NE;Sulaimon SS;Shen MM;Devere White RW;Borowsky AD
TP 53突变在人前列腺癌（CaP）中是常见的，在局部和转移性疾病中分别以约30%和约70%的频率发生。体外研究已经确定了几种常见的TP 53突变，除了功能丧失外，还具有特定的功能获得特性，包括在某些情况下促进CaP细胞去势抵抗（CR）生长的能力。到目前为止，缺乏合适的小鼠模型，禁止调查的作用，介导的CaP在体内进展的Tp 53突变。在这里，我们描述了突变型Tp 53（Tp 53 R270 H;相当于人类热点突变型R273 H）在小鼠前列腺上皮细胞中的条件表达的影响。杂合子“Tp 53 LSL-R270 H/+”[129 S4（Trp 53 tm 3 Tyj）]和“Nkx3.1-Cre”[129 S具有Tp 53 R270 H突变的前列腺特异性表达的（Nkx 3 - 1 tm 3（cre）Mms）]小鼠129 S4品系的小鼠（p53 R270 H/+ Nkx3.1-Cre小鼠）通过speed congenesis在FVB/N背景下繁殖以产生品系FVB. 129 S（Nkx 3-ltm 3（cre）Mms/wt）和同窝基因型阴性对照小鼠。这些突变小鼠的前列腺上皮内瘤（PIN）病变的发生率显着增加，这些出现更早，与Nkx3.1 haploinsufficient（Nkx3.1-Cre het）同窝小鼠相比，不表达TP 53突变。这些小鼠中的PIN病变显示出一致的进展，并且一些发展为具有高级别肉瘤样或上皮-间质转化（EMT）表型的浸润性腺癌。PIN病变与在PTEN条件性敲除小鼠中观察到的病变相似，有证据表明AKT活化伴随着肿瘤增殖。然而，侵袭性肿瘤表型在先前描述的前列腺肿瘤小鼠模型中很少见到。这些数据表明，Tp 53 R270 H突变在CaP起始中起作用。这一发现以前没有报道过。该模型的进一步表征，特别是在雄激素剥夺的情况下，应该允许进一步深入了解TP 53 R270 H突变介导CaP进展的机制。
Tp53 mutations are common in human prostate cancer (CaP), occurring with a frequency of ∼30% and ∼70% in localized and metastatic disease, respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain-of-function properties in addition to loss of function, including the ability to promote castration-resistant (CR) growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by Tp53 mutations in mediating CaP progression in vivo. Here, we describe the effects of conditional expression of a mutant Tp53 (Tp53R270H; equivalent to the human hotspot mutant R273H) in the prostate epithelium of mice. Heterozygous “Tp53LSL-R270H/+” [129S4(Trp53tm3Tyj)] and “Nkx3.1-Cre” [129S(Nkx3-1tm3(cre)Mms)] mice with prostate-specific expression of the Tp53R270H mutation (p53R270H/+ Nkx3.1-Cre mice) were bred onto an FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt); FVB.129S(Nkx3-1tm3(cre)Mms/wt) and littermate genotype negative control mice. These mutant mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions, and these appeared earlier, compared with the Nkx3.1 haploinsufficient (Nkx3.1-Cre het) littermate mice, which did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression and some developed into invasive adenocarcinoma with a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. However, the invasive tumor phenotype is rarely seen in previously described mouse models of prostatic neoplasia. These data indicate that the Tp53R270H mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insight into the mechanisms by which the Tp53R270H mutation mediates CaP progression.
登录
查看更多内容
影响因子：
4.6
作者：
Lin, Yongshun;Liu, Guoqin;Wang, Fen
通讯作者：
Wang, Fen
DOI：
10.1046/j.1464-410x.1997.03399.x
发表时间：
1997-02-01
期刊：
BRITISH JOURNAL OF UROLOGY
影响因子：
--
作者：
Byrne, RL;Horne, CHW;Hamdy, FC
通讯作者：
Hamdy, FC
影响因子：
6
作者：
Park, JH;Walls, JE;Cardiff, RD
通讯作者：
Cardiff, RD
影响因子：
23.4
作者：
Schlechte, H;Lenk, SV;Loening, SA
通讯作者：
Loening, SA
影响因子：
3.4
作者：
Shi, XB;Di Mauro, SM;White, RWD
通讯作者：
White, RWD