The role of Ink4a/Arf in ErbB2 mammary gland tumorigenesis.
Most human tumors display inactivation of the p53 and the p16(INK4)/pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16(INK4a) and p14(ARF) (murine p19(ARF)) proteins. p16(INK4a) is deleted in 40-60% of breast cancer cell lines, and p16(INK4a) inactivation by DNA methylation occurs in < or =30% of human breast cancers. In mice genetically heterozygous for p16(INK4a) or Ink4a/Arf, predisposition to specific tumor types is enhanced. Ink4a/Arf(+/-) mice have increased E micro -Myc-induced lymphomagenesis and epidermal growth factor receptor-induced gliomagenesis. ErbB2 (epidermal growth factor receptor-related protein B2) is frequently overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in vivo. We determined the role of heterozygosity at the Ink4a/Arf locus in ErbB2-induced mammary tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf(+/-) mice, mouse mammary tumor virus-ErbB2 Ink4a/Arf(wt) mammary tumors showed increased p16(INK4a), reduced Ki-67 expression, and reduced cyclin D1 protein but increased mammary tumor apoptosis with no significant change in the risk of developing mammary tumors. These studies demonstrate the contribution of Ink4a/Arf heterozygosity to tumor progression is tissue specific in vivo. In view of the important role of Ink4a/Arf in response to chemotherapy, these transgenic mice may provide a useful model for testing breast tumor therapies.
D'Amico
Mark
M
Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007, USA.
Wu
Kongming
K
Di Vizio
Dolores
D
Reutens
Anne T
AT
Stahl
Mark
M
Fu
Maofu
M
Albanese
Chris
C
Russell
Robert G
RG
Muller
William J
WJ
White
Michael
M
Negassa
Abdissa
A
Lee
Han-Woong
HW
DePinho
Ronald A
RA
Pestell
Richard G
RG
D000230:Adenocarcinoma / Q000473:pathology; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics; D003433:Crosses, Genetic; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D025803:Tumor Suppressor Protein p14ARF; D019938:Cyclin D1