Epidermal Growth Factor-Like Ligands in Breast Cancer.
Annual rept. 22 Aug 96-21 Aug 97
BURNHAM INST LA JOLLA CA
Pagination or Media Count:
Cripto-1 Cr-1 and Amphiregulin Ar are two EGF like growth factors that occur at higher levels in breast cancer cells and tissues. We have shown that they occur in the late stages of mammary cell proliferation in virgin, pregnant and lactating mouse mammary glands. In order to test the roles of Cr-1, we infected normal mouse mammary cells with retroviruses over-expressing Cr-1, or an antisense version, in order to inhibit the production of this polypeptide. Cr-1 stimulated proliferation but inhibited differentiation lactation. Reduction of Cr-1 decreased growth rate and increased apoptosis, but the cells were able to differentiate. Cr-1 overexpression appears not to be tumorigenic. The main approach for Ar will be to make transgenic mice overexpressing Ar in the mammary glands. We completely inactivated the Cr-1 genes in order to produce mice that expressed no Cr-1 in mammary glands as well as in all other tissues. To this end, we inactivated Cr-1 in embryo stem ES cells by homologous recombination and produced Cr-1 gene-targeted mice. Studies on these Cr-1-- cells showed that ES cell differentiation to cardiac myocytes was prevented. We have also produced knockout animals with Cr-1 null ES cells and shown that Cr-1 is essential for embryonic development. We made chimeric animals that will be useful for obtaining supporting data by isolating mammary cells that are Cr-1 null.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research