Abstract
Abstract The embryonic gene Cripto-1 (Cr-1) is expressed at very low levels in normal adult tissues and detected at high levels in several human tumors. We have previously found that Cr-1 can facilitate the proteolytic intracellular processing of all four Notch receptors. Transgenic mice overexpressing the Notch4 intracellular domain (Int3) in the mammary gland under the control of the whey acidic protein (WAP) promoter rapidly develop mammary hyperplasias and undifferentiated mammary adenocarcinomas in aged nulliparous females and after multiple cycles of pregnancy. Eighty percent of WAP-Int3 females develop mammary tumors by the second pregnancy. To assess the contribution of Cr-1 in the hyperplasias and tumors that arise in transgenic WAP-Int3 mice, we developed a bi-transgenic mouse model lacking one allele of Cr-1, by crossing the knock-in Cr-1/LacZ mice (containing a promoter-less bacterial β-galactosidase gene which disrupts one of the Cr-1 alleles) to WAP-Int3 transgenic mice. We found a 90% reduction in the frequency of mammary hyperplasias in these Cr-1/LacZ/WAP-Int3 mice in comparison to WAP-Int3 mice. Additionally, in the absence of one allele of Cr-1, Int3-induced transformation of mouse mammary epithelial cells was delayed in vivo, and additional cycles of pregnancy were required to observe tumor growth. Notably, only 20% of the Int3/Cr-1 haploinsufficient mice developed mammary tumors by the second pregnancy, as compared to 80% of those mice that preserve two alleles of Cr-1. The few tumors derived from these mice also showed a significantly more differentiated histology in comparison to those tumors that arose from mice preserving both alleles of Cr-1. We are currently generating a mouse model which conditionally lacks the two alleles of Cr-1 in the mammary gland, what should better address our question regarding the functional significance of Cr-1 in the development of Int3-induced mammary tumorigenesis. Citation Format: Maria Cristina Rangel, Ahmed Raafat, Nadia P. Castro, Malgorzata Klauzinska, Hideaki Karasawa, Alyson Baker, Robert Callahan, David S. Salomon. Mammary tumorigenesis in haploinsufficient Cripto-1 mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-261. doi:10.1158/1538-7445.AM2013-LB-261
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