Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency.
Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium, and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor-positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. It is interesting that this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap1 co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb deficiency, such as mammary carcinoma.
Cheng
L
L
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853-6401, USA.
Zhou
Z
Z
Flesken-Nikitin
A
A
Toshkov
I A
IA
Wang
W
W
Camps
J
J
Ried
T
T
Nikitin
A Y
AY
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D005784:Gene Amplification; D042822:Genomic Instability; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D010750:Phosphoproteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases