title: Responsiveness ofBrca1andTrp53Deficiency-Induced Mammary Preneoplasia to Selective Estrogen Modulators versus an Aromatase Inhibitor inMus musculus.
abstract: An intervention study initiated at age 4 months compared the impact of tamoxifen (25 mg), raloxifene (22.5 mg), and letrozole (2.5 mg) administered by 60-day release subcutaneous pellet on mammary preneoplasia prevalence at age 6 months in conditional genetically engineered mouse models with different Breast cancer 1 (Brca1) gene dosages targeted to mammary epithelial cells and germline Tumor protein P53 (Trp53) haploinsufficiency (10-16/cohort). The proportion of unexposed control mice demonstrating mammary preneoplasia at age 6 months was highest inBrca1fl11/fl11/Cre/p53-/+(54%) mice followed byBrca1WT/fl11/Cre/p53-/+mice (30%). By age 12 months, invasive mammary cancers appeared in 80% ofBrca1fl11/fl11/Cre/p53-/+and 42% ofBrca1WT/fl11/Cre/p53-/+control unexposed mice. The spectrum of cancer histology was similar in both models without somatic mutation of the nongenetically engineeredBrca1, Trp53, Brca2, or Death-associated protein kinase 3 (Dapk3) alleles. Two-month exposure to tamoxifen, raloxifene, and letrozole significantly reduced estrogen-mediated tertiary branching by 65%, 71%, and 78%, respectively, inBrca1fl11/fl11/Cre/p53-/+mice at age 6 months. However, only letrozole significantly reduced hyperplastic alveolar nodules (HAN) prevalence (by 52%) and number (by 30%) and invasive cancer appeared despite tamoxifen exposure. In contrast, tamoxifen significantly reduced HAN number by 95% inBrca1WT/fl11/Cre/p53-/+mice. Control mice with varying combinations of the different genetically modified alleles andMMTV-Cretransgene demonstrated that the combination ofBrca1insufficiency andTrp53haploinsufficiency was required for appearance of preneoplasia and no individual genetic alteration confounded the response to tamoxifen. In summary, although specific antihormonal approaches showed effectiveness, withBrca1gene dosage implicated as a possible modifying variable, more effective chemopreventive approaches forBrca1mutation-induced cancer may require alternative and/or additional agents.Cancer Prev Res; 10(4); 244-54. ©2017 AACR.
authors.affiliation: Graduate School of Arts and Science, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.|Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Sahar J
authors.initials: SJ
authors.lastname: Alothman
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: David S
authors.initials: DS
authors.lastname: Goerlitz
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Md
authors.initials: M
authors.lastname: Islam
authors.affiliation: Department of Biostatistics, Bioinformatics & Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Archana
authors.initials: A
authors.lastname: Kishore
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Redha I
authors.initials: RI
authors.lastname: Azhar
authors.affiliation: Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.|Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Bhaskar V
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. paf3@georgetown.edu.|Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.|Department of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Furth
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D019313:BRCA1 Protein; D005260:Female; D000077289:Letrozole; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology; D011230:Precancerous Conditions / Q000235:genetics* / Q000517:prevention & control; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D047072:Aromatase Inhibitors; D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; D009570:Nitriles; D020845:Selective Estrogen Receptor Modulators; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D000077289:Letrozole