title: BCL-2 hypermethylation is a potential biomarker of sensitivity to antimitotic chemotherapy in endocrine-resistant breast cancer.
abstract: Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P = 0.019) when compared with gene expression (n = 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease.
authors.affiliation: Corresponding Author: Andrew Stone, Garvan Institute of Medical Research, L9 TKCC, 370 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. a.stone@garvan.org.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Fatima
authors.initials: F
authors.lastname: Valdes-Mora
authors.forename: Rachael A
authors.initials: RA
authors.lastname: McCloy
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Sergio
authors.forename: David
authors.initials: D
authors.lastname: Gallego-Ortega
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Caldon
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
mesh_terms: D050256:Antimitotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D009596:Nitrophenols / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D011621:Pteridines; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; C518477:BI 2536; D001549:Benzamides; D015415:Biomarkers; D001713:Biphenyl Compounds; D006574:Heterocyclic Compounds, 2-Ring; D009596:Nitrophenols; D010879:Piperazines; D011621:Pteridines; D013449:Sulfonamides; D017239:Paclitaxel; D015739:Nocodazole