Abstract 2304: Biologically distinct mammary tumors develop from Trp53 null tissue transplanted to juvenile versus adult gland.

Abstract

Abstract The biology of the organism is a key regulator of breast cancer development. Our previous work showed that irradiating the host accelerated the development of carcinomas from unirradiated Trp53 null mammary fragments transplanted into the inguinal fat pads previously divested of endogenous epithelia (Nguyen et al., Cancer Cell, 2011). In this report, we investigated the age of transplantation by comparing carcinogenesis in Trp53 null mammary outgrowths that were transplanted during pubertal, 5 week-old mice compared to 10 week-old adult hosts. Tumors arising over the course of a year from Trp53 null tissue transplanted into adult hosts (AH) (n=26), were compared to tumors arising following transplantation in juvenile hosts (JH) (n=55). The rate of tumor occurrence was not significantly different as a function of the transplantation age but once detected, JH tumors grew several times faster. JH tumors were more perfused, as indicated by 2-fold larger blood vessels (p=0.015), and exhibited a 2-fold higher mitotic index (p=0.009) compared to AH tumors. Tumors transplanted at either age were predominantly ER+ (80% JH vs. 60% AH), but more tumor cells were ER immunoreactive as measured by the Allred score in JH tumors compared to AH tumors (p=0.0001). Microarray analysis of 10 JH and 6 AH tumors identified 119 genes that were modulated by at least 1.5-fold in JH tumors. Main biological processes enriched in JH tumors were organ morphology, proliferation, and lipid metabolism. The resulting profile revealed a luminal transcriptional program in JH tumors that included expression of Foxa1 and Areg; Foxa1 protein expression in JH tumors was confirmed by immunohistochemistry. The distinct biology of tumors arising from tissue undergoing morphogenesis in the context of puberty suggests that: (1) the window of susceptibility for breast cancer involves host biology during puberty; and (2) that the tumor intrinsic subtype is not necessarily epithelial autonomous, but can be influenced by the host environment. Supported by DOD-BCRP and DOE Low Dose Radiation Program. Citation Format: David H. Nguyen, Jian-Hua Mao, Mary Helen Barcellos-Hoff. Biologically distinct mammary tumors develop from Trp53 null tissue transplanted to juvenile versus adult gland. [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 2304. doi:10.1158/1538-7445.AM2013-2304