Most human tumors display inactivation of the p53 and the p16IK4/ pRb pathway. The Ink4a/alternative reading frame (ARF) locus encodes the p16INK4a and p14ARF (murine p19ARF) proteins. p16INK4a is deleted in 40-60% of breast cancer cell lines, and p16INKa inactivation by DNA methylation occurs in ≤30% of human breast cancers. In mice genetically heterozygous for p16INK4a 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 tumorigenesis. Compared with mouse mammary tumor virus-ErbB2 Ink4a/Arf+/- mice, mouse mammary tumor virus-ErbB2 Ink4a/Arfwt mammary tumors showed increased p16INK4a, 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.
|Original language||English (US)|
|Number of pages||8|
|Publication status||Published - Jun 15 2003|
All Science Journal Classification (ASJC) codes
- Cancer Research