title: Different epigenetic mechanisms of ERα implicated in the fate of fulvestrant-resistant breast cancer.
abstract: Approximately 70% of breast cancers express estrogen receptor α (ERα), which plays critical roles in breast cancer development. Fulvestrant has been effectively used to treat ERα-positive breast cancer, although resistance remains a critical problem. To elucidate the mechanism of resistance to fulvestrant, we established fulvestrant-resistant cell-lines named MFR (MCF-7 derived fulvestrant resistance) and TFR (T-47D derived fulvestrant resistance) from the ERα-positive luminal breast cancer cell lines MCF-7 and T-47D, respectively. Both fulvestrant-resistant cell lines lost sensitivity to estrogen and anti-estrogens. We observed diminished ERα expression at both the protein and mRNA levels. To address the mechanism of gene expression regulation, we examined epigenetic alteration, especially the DNA methylation level of ERα gene promoters. MFR cells displayed high methylation levels upstream of the ERα gene, whereas no change in DNA methylation was observed in TFR cells. Hence, we examined the gene expression plasticity of ERα, as there are differences in its reversibility following fulvestrant withdrawal. ERα gene expression was not restored in MFR cells, and alternative intracellular phosphorylation signals were activated. By contrast, TFR cells exhibited plasticity of ERα gene expression and ERα-dependent growth; moreover, these cells were resensitized to estrogen and anti-estrogens. The difference in epigenetic regulation among individual cells might explain the difference in the plasticity of ERα expression. We also identified an MFR cell-activating HER/Src-Akt/MAPK pathway; thus, the specific inhibitors effectively blocked MFR cell growth. This finding implies the presence of multiple fulvestrant resistance mechanisms and suggests that the optimal therapies differ among individual tumors as a result of differing epigenetic mechanisms regulating ERα gene expression.
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Nagatomo
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan; Surgical Oncology, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Fujii
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan; Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hanamura
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Gohno
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate Tohoku University School of Medicine, Sendai, Japan; Center for Regulatory Epigenome and Diseases, Graduate Tohoku University School of Medicine, Sendai, Japan. Electronic address: shin@med.tohoku.ac.jp.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Hayashi
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000077267:Fulvestrant; D004958:Estradiol
keywords: Breast cancer; DNA methylation; Endocrine therapy resistance; Estrogen receptor α; Fulvestrant