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 ≤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 Eμ-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 tunorigenesis. 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.