Cooperativity of Rb, Brca1, and p53 in Malignant Breast Cancer Evolution

被引:18
作者
Kumar, Prashant [1 ]
Mukherjee, Malini [2 ]
Johnson, Jacob P. S. [1 ]
Patel, Milan [1 ]
Huey, Bing [3 ]
Albertson, Donna G. [3 ]
Simin, Karl [1 ]
机构
[1] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA
[2] Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat Hematol Oncol, Houston, TX 77030 USA
[3] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
来源
PLOS GENETICS | 2012年 / 8卷 / 11期
关键词
TO-MESENCHYMAL TRANSITION; BASAL-LIKE; MAMMARY PROGENITORS; TUMOR-SUPPRESSOR; CLAUDIN-LOW; LUMINAL-B; MOUSE; INACTIVATION; SUBTYPES; MICE;
D O I
10.1371/journal.pgen.1003027
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.
引用
收藏
页数:13
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