Abstract 2522: Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis

Amphiregulin (AREG) is an estrogen-responsive ligand of the epidermal growth factor receptor. Mice with germline deletion of AREG are defective in pubertal mammary expansion. Using shRNA, we have previously reported that the estrogen-responsive growth of MCF7 xenograft tumors in immunocompromised mice is also AREG-dependent. Here we use a series of genetically engineered mouse AREG models (lacZ-knock-in, conditional knockout and germline knockout) to address two outstanding questions: (1) Among the numerous AREG-expressing cell types in the mammary gland and stroma, does the requirement for AREG in mammary gland development reside specifically in the luminal epithelial cells? (2) Is AREG required for mammary tumorigenesis in immunologically-intact mice? An initial characterization of mammary gland development using an AREG-lacZ knock-in allele identified AREG promoter activity in the luminal epithelial but not the myoepithelial compartment. We generated AREGfl/fl mice and achieved luminal epithelial cell specific AREG deletion using MMTV-Cre. Mice lacking AREG in the luminal epithelial compartment (but otherwise proficient in AREG expression) phenocopied the deficit in outgrowth seen in the AREG germline deletion, indicating that luminal epithelial AREG expression is essential for mammary gland development. To determine the extent to which AREG deletion affects mammary tumor latency and multiplicity in immune-intact animals, we used a Cre-regulated model of p53 mutation in mammary tissue (MMTV-Cre x p53LSL-R172H). We used this p53-dependent model to generate at-risk cohorts with AREG deficient (AREG-/-) and AREG proficient (AREG+/+ & AREG+/-) genotypes. Although the cohorts are still maturing, the median age of mammary tumors observed in AREG proficient mice is 258 days (median tumor multiplicity is 2 per animal), while only a single tumor has been detected in the AREG deficient cohort (at 415 days). Together, these data point to two temporally distinct roles for amphiregulin–an essential function in mammary ductal expansion during puberty and a subversion of this developmental role during tumorigenesis later in life. Citation Format: Kristopher A. Lofgren, David R. Meier, Megan A. Girtman, Esther A. Peterson, E. Charles Jenkins, Paraic A. Kenny. Luminal epithelial cell expression of amphiregulin is required for mammary gland development and facilitates mutant p53-driven tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Resea