Constitutive expression of AhR and BRCA-1 promoter CpG hypermethylation as biomarkers of ERα-negative breast tumorigenesis. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Romagnolo, Donato; Papoutsis, Andreas; Laukaitis, Christina; Selmin, Ornella
• Is Part Of: BMC cancer. Volume 15:Issue 1(2015)
• Page Start: 1
• Page End: 11
• Publication Date: 2015-12
• Subjects: BRCA-1 -- AhR -- CpG methylation -- Epigenetics -- SAhRMs -- ERα -- Breast cancer; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-2044-9
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background Only 5–10 % of breast cancer cases is linked to germline mutations in theBRCA-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 mutatedBRCA-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 theBRCA-1 gene may provide clues for breast cancer therapy. Methods We evaluatedBrca-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 hypomethylatedBRCA-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 ofAhR andBRCA-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. Results Mammary tumors induced with DMBA had reduced BRCA-1 and ERα expression; higherBrca-1 promoter CpG methylation; increased expression ofAhr and its downstream targetCyp1b1 ; and higher proliferation markersCcnd1 (cyclin D1) andCdk4 . 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 ofCYP1A1 compared toCYP1B1 . Conversely, in MCF-7 cells, αNF antagonized estradiol-dependent activation of BRCA-1 without effects on expression of ERα. TNBC exhibited increased basalAhR andBRCA-1 promoter CpG methylation compared to LUM-A, LUM-B, and HER-2-positive breast tumors. Conclusions Constitutive AhR expression coupled toBRCA-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 hypermethylatedBRCA-1 gene.