Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells
Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells
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DOI：
10.1593/neo.08120
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发表时间：
2008-05-01
期刊：
影响因子：
4.8
通讯作者：
Futscher, Bernard W.
中科院分区：
文献类型：
--
作者：
Junk, Damian J.;Vrba, Lukas;Futscher, Bernard W.
p53的异常发生在大多数（如果不是全部）人类癌症中。在乳腺癌中，p53突变是与单个基因相关的最常见的遗传缺陷。永生化的人乳腺上皮细胞类似于异常乳腺组织生长的最早形式，但不表达许多恶性相关表型。我们通过用四种不同的突变型p53构建体感染表达野生型p53的hTERT-HME 1永生化人乳腺上皮细胞来建立人乳腺上皮肿瘤发生模型，以确定p53突变对肿瘤表型演变的作用。我们证明，不同的突变型/野生型p53杂合子模型产生的功能丧失，显性负活性，并诱导不同程度的侵入性潜力的功能活动的增益谱。我们认为，该模型可用于阐明发生在人类乳腺上皮肿瘤发生的早期阶段的变化。这些变化可能构成新的生物标志物或揭示新的治疗方式，可以抑制从原发性乳腺疾病进展为转移性乳腺疾病。
Aberrations of p53 occur in most, if not all, human cancers. In breast cancer, p53 mutation is the most common genetic defect related to a single gene. Immortalized human mammary epithelial cells resemble the earliest forms of aberrant breast tissue growth but do not express many malignancy-associated phenotypes. We created a model of human mammary epithelial tumorigenesis by infecting hTERT-HME1 immortalized human mammary epithelial cells expressing wild-type p53 with four different mutant p53 constructs to determine the role of p53 mutation on the evolution of tumor phenotypes. We demonstrate that different mutant/wild-type p53 heterozygous models generate loss of function, dominant negative activity, and a spectrum of gain of function activities that induce varying degrees of invasive potential. We suggest that this model can be used to elucidate changes that occur in early stages of human mammary epithelial tumorigenesis. These changes may constitute novel biomarkers or reveal novel treatment modalities that could inhibit progression from primary to metastatic breast disease.