Transgenic models to assess the role of p27 in breast cancer

Development of the normal breast and breast carcinogenesis involves a complex interplay between growth factors, steroids, activation of oncogenes and inactivation of tumor suppressor genes. The transgenic mouse has served as a useful model for investigation of genes required for mammary tumorigenesis. Breast tumorigenesis is induced by targeted overexpression of several different oncogenes including Myc , Erb-B2(Neu), Ras, Src, cyclin D1 and cyclin E.The current studies focus on Erb-B2 (Neu) oncogene-induced tumors because of its frequent involvement in human breast cancer and overexpression of Neu in transgenic mice under the control of the MMTV-LTR induces mammary adenocarcinomas with high frequency. Reduced p27 tumor suppressor levels are found in a variety of tumors including breast cancers. Reduced p27 levels have independent prognostic significance in a subset of tumors. Although loss of a single p27 allele is not uncommon in human tumors the second allele is frequently wild type. Thus p27 does not fit the classic tumor suppressor paradigm and raises the question whether p27 may function as a dose-dependent fashion. The aim of this study is to determine the role of p27 as a mammary tumor suppressor in vivo. Transgenic mice overexpressing ErbB-2 in the mammary gland (MMTV-Neu) will therefor be mated with p27-/- mice. The second aim is to determine the effect of p27 overexpression on Neu-induced mammary tumors. These studies will be performed in cultured cells and in vivo in FVB and nude mice. We will use a tet-regulated p27 system previously described by this laboratory and determine the effect of p27 dose on tumor growth. Initial studies from our laboratory suggest a more rapid rate of onset of tumorigenesis amongst the MMTV-Neu transgenic mice heterozygous for p27 compared with animals with both p27 alleles. Animals that are nullizygous for p27 develop tumors in a delayed fashion. Together these preliminary data are consistent with findings in human tumors and recent perspectives on the dual function of the Cyclin Dependent Kinase Inhibitors to function as both tumor suppressors and tumor promoting proteins, depending upon the stoichiometry. Identifying p27 abundance as a rate-limiting step in breast cellular proliferation may provide a better understanding of the molecular mechanism governing cellular proliferation and a rationale basis for alternative forms of breast cancer therapy.