Phosphatase and tensin homologue deleted on chromosome 10 deficiency accelerates tumor induction in a mouse model of ErbB-2 mammary tumorigenesis.
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and amplification or elevated expression of ErbB-2 are both involved in human breast cancer. To directly test the importance of these genetic events in mammary tumorigenesis, we have assessed whether mammary-specific disruption of PTEN could cooperate with activation of ErbB-2. Transgenic mice expressing ErbB-2 under the transcriptional control of its endogenous promoter (ErbB-2(KI)) were interbred with mice carrying conditional PTEN alleles and an MMTV/Cre transgene. Loss of one or both PTEN alleles resulted in a dramatic acceleration of mammary tumor onset and an increased occurrence of lung metastases in the ErbB-2(KI) strain. Tumor progression in PTEN-deficient/ErbB-2(KI) strains was associated with elevated ErbB-2 protein levels, which were not due to ErbB-2 amplification or to a dramatic increase in ErbB-2 transcripts. Moreover, the PTEN-deficient/ErbB-2(KI)-derived mouse mammary tumors display striking morphologic heterogeneity in comparison with the homogeneous pathology of the ErbB-2(KI) parental strain. Therefore, inactivation of PTEN would not only have a dramatic effect on ErbB-2-induced mammary tumorigenesis but would also lead to the formation of mammary tumors that, in part, display pathologic and molecular features associated with the basal-like subtype of primary human breast cancer.
Dourdin
Nathalie
N
Molecular Oncology Group, McGill University Health Center, Montreal, Quebec, Canada.
Schade
Babette
B
Lesurf
Robert
R
Hallett
Michael
M
Munn
Robert J
RJ
Cardiff
Robert D
RD
Muller
William J
WJ
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D033481:Chromosomes, Mammalian; D004195:Disease Models, Animal; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D019656:Loss of Heterozygosity; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics
D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; C494929:PTEN protein, human; C487757:Pten protein, mouse