Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts.
Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts.
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DOI：
10.3892/ijo_00000768
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发表时间：
2010-11
影响因子：
5.2
通讯作者：
Salisbury JL
中科院分区：
文献类型：
--
作者：
D'Assoro AB;Leontovich A;Amato A;Ayers-Ringler JR;Quatraro C;Hafner K;Jenkins RB;Libra M;Ingle J;Stivala F;Galanis E;Salisbury JL
染色体不稳定(CIN)的发展和随之而来的表型异质性是乳腺癌进展过程中的常见事件。具有广泛染色体异常的乳腺癌表现出更具侵袭性的行为，其特征是化疗耐药和引起远处转移的倾向。肿瘤抑制基因P53通过DNA损伤后细胞周期检查点的激活和中心体复制的控制，在维持染色体稳定和组织动态平衡方面发挥着关键作用，从而确保细胞分裂过程中染色体的平等分离。此外，P53抑制CD44的表达和干细胞样特性的获得，这些特性与上皮向间充质转化(EMT)和转移有关。在这项研究中，我们使用了内源性野生型p53的MCF-7乳腺癌细胞和从vMCF-7DNP53肿瘤移植瘤中重新培养的细胞。我们进行了一项综合的转录组和细胞遗传学分析，以表征乳腺癌进展过程中p53功能丧失、EMT和随后建立的侵袭基因特征之间的机制联系。我们证明，P53功能的丧失驱动了早期转录组的变化，这些转录组变化负责细胞增殖、EMT和生存，而在体内肿瘤进展过程中发生的进一步转录组变化与CIN的发展有机械联系，从而导致更具侵袭性和转移性的乳腺癌表型。在这里，我们发现了独特的新的非规范转录组网络，涉及细胞增殖、EMT、化疗耐药和侵袭，这些网络是在体外取消P53功能和在体内发展CIN后产生的。这些研究还具有重要的翻译意义，因为这里发现的一些结节基因是“可用药的”，使它们成为治疗乳腺癌的合适分子靶点，这些乳腺癌显示出突变的P53、EMT、CIN和高转移潜力。
Development of chromosomal instability (CIN) and consequent phenotypic heterogeneity represent common events during breast cancer progression. Breast carcinomas harboring extensive chromosomal aberrations display a more aggressive behavior characterized by chemoresistance and the propensity to give rise to distant metastases. The tumor suppressor p53 plays a key role in the maintenance of chromosomal stability and tissue homeostasis through activation of cell cycle checkpoints following DNA damage and control of centrosome duplication that ensures equal chromosome segregation during cell division. Furthermore, p53 suppresses CD44 expression and the acquisition of stem cell-like properties responsible for epithelial to mesenchymal transition (EMT) and metastasis. In this study we employed MCF-7 breast cancer cells with endogenous wild-type p53, an engineered MCF-7 variant (vMCF-7DNP53) overexpressing a dominant negative p53val135 mutant, and cells re-cultured from vMCF-7DNP53 tumor xenografts. We carried out an integrative transcriptome and cytogenetic analysis to characterize the mechanistic linkage between loss of p53 function, EMT and consequent establishment of invasive gene signatures during breast cancer progression. We demonstrate that abrogation of p53 function drives the early transcriptome changes responsible for cell proliferation, EMT and survival, while further transcriptome changes that occur during in vivo tumor progression are mechanistically linked to the development of CIN leading to a more invasive and metastatic breast cancer phenotype. Here we identified distinct novel non-canonical transcriptome networks involved in cell proliferation, EMT, chemoresistance and invasion that arise following abrogation of p53 function in vitro and development of CIN in vivo. These studies also have important translational implications since some of the nodal genes identified here are ‘druggable’ making them appropriate molecular targets for the treatment of breast carcinomas displaying mutant p53, EMT, CIN and high metastatic potential.
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影响因子：
56.9
作者：
Schrock, E;duManoir, S;Ried, T
通讯作者：
Ried, T
影响因子：
5.3
作者：
Adon, Arsene M.;Zeng, Xiangbin;Saavedra, Harold I.
通讯作者：
Saavedra, Harold I.
DOI：
10.1073/pnas.0909129107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Menendez, Daniel;Inga, Alberto;Resnick, Michael A.
通讯作者：
Resnick, Michael A.
影响因子：
--
作者：
SPURBECK, JL;CARLSON, RO;DEWALD, GW
通讯作者：
DEWALD, GW
影响因子：
8
作者：
D'Assoro, AB;Busby, R;Salisbury, JL
通讯作者：
Salisbury, JL