Abstract
Abstract
Background: Women carrying one mutated copy of BRCA1 are disposed to developing breast cancer. BRCA1-mutation-related cancers often harbor TRP53 mutations. Previously established genetically engineered mouse (GEM) models with spontaneous mammary cancer development have both copies of Brca1 disrupted in combination with Trp53 haploinsufficiency. Here we characterized cancer development in GEM with only one copy of Brca1 disrupted in mammary epithelial cells using Cre-Lox technology in combination with germ-line Trp53 haploinsufficiency. Methods: From our Brca1f11fT11/MMTV-Cre/Trp53+/− breeding program we noted mammary cancer development in female Brca1f11/WT11/MMTV-Cre/Trp53+/− mice. The time-course of mammary hyperplasia and cancer development was characterized in these mice. Mice were euthanized at age 6 months (n = 9) or when the largest tumor reached 1 cm3 or at 12 months if no tumor developed (n = 12). Cancers were resected, inguinal mammary glands processed for histology and thoracic mammary glands flash frozen or processed for primary cell culture. Hyperplastic alveolar nodules (HANs) and branching patterns were detected using inguinal mammary gland whole mounts. Histology was read on H&E stained slides and immunohistochemistry (IHC) performed for ERα, PGR and HER2 on cancer specimens. Results: Thirty-three percent of the mice developed palpable mammary tumors by age 12 months. Forty-four percent of the mice exhibited HANs at age 6 months and 56% at age 12 months. One mouse developed a female reproductive tract cancer. Three mice developed single palpable mammary adenocarcinomas. One mouse developed two cancers, one palpable spindloid and one non-palpable anaplastic carcinoma. Two adenocarcinomas have completed IHC studies and are ER/PGR/HER2 negative. Multilayered ductal hyperplasia was present only in 12-month-old mice (89%). Two-layered lobular-type hyperplasia was found in 33% of 6-month-old and 100% of 12-month-old mice. Primary cell cultures were established from both cancers attempted. Conclusions: Here we report development of a Brca1 insufficiency mouse model more representative of disease development in women who carry only one allele with a BRCA1-mutation. Similar to models with both Brca1 copies disrupted, Trp53 haploinsufficiency was required for cancer progression. The spectrum of mammary cancer histology was similar to that previously reported when both Brca1 alleles were disrupted. This model represents a tool for investigation of preventive strategies in the face of Brca1 and Trp53 haploinsufficiency and study of possible interactions between this genetic background and genetic and environmental factors that may promote cancer development.
Citation Format: Sahar Alothman, Svenja Groeneveld, Ahmad Alamri, Bhaskar Kallakury, Priscilla A. Furth. Spontaneous mammary cancer development in genetically engineered mice with only one copy of Brca1 disrupted in combination with Trp53 haploinsufficiency. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2286. doi:10.1158/1538-7445.AM2015-2286