Preneoplastic mammary tumor markers: Cripto and Amphiregulin are overexpressed in hyperplastic stages of tumor progression in transgenic mice.

Amphiregulin (Ar) and Cripto (Cr) are autocrine growth factors for mammary cells and both have been observed to exhibit high expression in human mammary tumors, in contrast with adjacent tissues. To investigate whether Ar and Cr play roles in the progression of mammary cell proliferation to unregulated growth and tumor formation, the levels of expression were examined in transgenic mice (TGM) that over-express several different oncogenes: MMTV-Polyoma virus middle T antigen (MMTV-PyMT), MMTV-c-ErbB2 (c-neu, HER2) and MT-hTGF alpha. These transgenic mice all produce mammary tumors but with different rates of progression. The levels of Ar were induced up to 10-fold in association with hyperplasia in 2 of the TGM. Cr overexpression was consistently observed in hyperplastic mammary glands in all the animal models, decreasing in overt tumors in 2 of the TGM models. In MMTV-PyMT mammary glands, the levels of Cr expression rose 7- to 10-fold in hyperplastic tissue and 25-fold the levels in tumors compared to age-matched transgene negative mice. Ar and especially Cr thus should have potential value as markers of preneoplastic change in mammary tissue.