Abstract
Abstract Background: Reduced BRCA1 and/or p53 function in mammary tissue is associated with tamoxifen resistance in vivo and in vitro. A shift towards tamoxifen agonist activity with reduced BRCA1 function is found in vitro. The goal of this study was to identify which combinations of disrupted Brca1 and p53 gene(s) result in preneoplasia and test for tamoxifen resistance and activity in vivo. Methods: Brca1 homozygous and heterozygous conditional exon 11 knockout and wildtype mice all carrying MMTV-Cre on a p53 wildtype or haploinsufficient background received a 25 mg 60-day constant release tamoxifen pellet (Innovative Research of America, Sarasota, FL) or sham surgery at age 4m, euthanasia/necropsy at age 6m and mammary glands taken for whole mount, histological and western blot (pERK / ERK and pHistone/Histone ratios, cleaved PARP). Cohorts of untreated Brca1f11/WT11/MMTV-Cre/p53+/- and Brca1f11/f11/MMTV-Cre/p53+/- mice were observed to age 12m for mammary cancer. Fisher's exact and Kruskal-Wallis tests were used for statistical analyses. Results: Hyperplastic alveolar nodules at age 6m and cancer development at age 12m were limited to Brca1f11/WT11/MMTV-Cre/p53+/- and Brca1f11/f11/MMTV-Cre/p53+/- mice. Ductal hyperplasia was detected in Brca1f11/WT11/MMTV-Cre/p53+/+, Brca1f11/f11/MMTV-Cre/p53+/+, Brca1f11/WT11/MMTV-Cre/p53+/-, Brca1f11/f11/MMTV-Cre/p53+/- and Brca1WT11/WT11/MMTV-Cre/p53+/- but not wildtype mice. Only Brca1f11/WT11/MMTV-Cre/p53+/+ and Brca1f11/f11/MMTV-Cre/p53+/+ mice showed significant reductions in ductal hyperplasia on tamoxifen. In contrast prevalence of ductal hyperplasia and/or hyperplastic alveolar nodules was not altered by tamoxifen in Brca1WT11/WT11/MMTV-Cre/p53+/-, Brca1f11/WT11/MMTV-Cre/p53+/- or Brca1f11/f11/MMTV-Cre/p53+/- mice. No evidence of tamoxifen activity was found as proliferation measures were either reduced (percentage mammary epithelial cells with nuclear-localized PCNA) or unchanged (pERK / ERK and pHistone/Histone ratios) with tamoxifen treatment in all genotypes. Cleaved PARP was detected in tamoxifen-treated but not control mice. Conclusions: p53 haploinsufficiency in combination with loss of either one or two copies of intact Brca1 was sufficient to induce hyperplastic alveolar nodules and cancer. Tamoxifen resistance was found in all p53 haploinsufficient mice. There was no indication of a shift towards tamoxifen agonist activity, that is, no increase in expression of any proliferative marker with Brca1 deficiency, and apoptosis was activated. Alternative pathways for tamoxifen resistance involving p53 may be responsible for the tamoxifen resistance observed in Brca1 deficient preneoplastic mammary epithelial cells. Citation Format: Sahar J. Alothman, Weisheng Wang, Priscilla A. Furth. Tamoxifen fails to induce regression of mammary preneoplasia in mice lacking either one or two intact BRCA1 genes in combination with p53 haploinsufficiency but without evidence of in vivo agonist activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2014-5576
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