Abstract

BackgroundOnly 5–10 % of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life. Conversely, sporadic breast tumors, which represent 90-95 % of breast malignancies, have lower BRCA-1 expression, but not mutated BRCA-1 gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Therefore, understanding if changes in expression and/or activation of the AhR are associated with somatic inactivation of the BRCA-1 gene may provide clues for breast cancer therapy.MethodsWe evaluated Brca-1 CpG promoter methylation and expression in mammary tumors induced in Sprague–Dawley rats with the AhR agonist and mammary carcinogen 7,12-dimethyl-benzo(a)anthracene (DMBA). Also, we tested in human estrogen receptor (ER)α-negative sporadic UACC-3199 and ERα-positive MCF-7 breast cancer cells carrying respectively, hyper- and hypomethylated BRCA-1 gene, if the treatment with the AhR antagonist α-naphthoflavone (αNF) modulated BRCA-1 and ERα expression. Finally, we examined the association between expression of AhR and BRCA-1 promoter CpG methylation in human triple-negative (TNBC), luminal-A (LUM-A), LUM-B, and epidermal growth factor receptor-2 (HER-2)-positive breast tumor samples.ResultsMammary tumors induced with DMBA had reduced BRCA-1 and ERα expression; higher Brca-1 promoter CpG methylation; increased expression of Ahr and its downstream target Cyp1b1; and higher proliferation markers Ccnd1 (cyclin D1) and Cdk4. In human UACC-3199 cells, low BRCA-1 was paralleled by constitutive high AhR expression; the treatment with αNF rescued BRCA-1 and ERα, while enhancing preferential expression of CYP1A1 compared to CYP1B1. Conversely, in MCF-7 cells, αNF antagonized estradiol-dependent activation of BRCA-1 without effects on expression of ERα. TNBC exhibited increased basal AhR and BRCA-1 promoter CpG methylation compared to LUM-A, LUM-B, and HER-2-positive breast tumors.ConclusionsConstitutive AhR expression coupled to BRCA-1 promoter CpG hypermethylation may be predictive markers of ERα-negative breast tumor development. Regimens based on selected AhR modulators (SAhRMs) may be useful for therapy against ERα-negative tumors, and possibly, TNBC with increased AhR and hypermethylated BRCA-1 gene.

Highlights

  • 5–10 % of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life

  • This study reports that rat mammary tumors induced with the aromatic hydrocarbon receptor (AhR)-agonist 7,12-dimethyl-benzo(a)anthracene (DMBA) [48] had augmented CpG methylation of the Brca-1 gene; higher expression of Ahr, Cyp1b, and proliferation markers (Cdk4, Ccnd1); and diminished expression of BRCA-1 and estrogen receptor-α (ERα)

  • The upregulation of Ahr and Cyp1b1 were paralleled by increased Brca-1 CpG methylation, and reduced expression of BRCA-1 and ERα in mammary tumors induced with DMBA

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Summary

Introduction

5–10 % of breast cancer cases is linked to germline mutations in the BRCA-1 gene and occurs early in life. Sporadic breast tumors, which represent 90-95 % of breast malignancies, have lower BRCA-1 expression, but not mutated BRCA-1 gene, and tend to occur later in life in combination with other genetic alterations and/or environmental exposures. The latter may include environmental and dietary factors that activate the aromatic hydrocarbon receptor (AhR). Sporadic breast tumors tend to display characteristics of BRCA-1 mutation cancers (i.e. BRCAness) [24] These include a high degree of correlation (~75 %) between hypermethylation of the BRCA-1 and ERα (ESR1) genes, and reduced expression of BRCA-1 and ERα [25,26,27,28,29]. Unraveling the cellular processes that place CpG methylation marks on the BRCA1 gene [30] may assist with the formulation of therapies against loss of BRCA-1 expression in BRCA-1 mutation carriers [31] and non-BRCA-1 mutation patients [32]

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