title: Estrogen receptor activation by tobacco smoke condensate in hormonal therapy-resistant breast cancer cells.
abstract: The relationship between tobacco smoke and breast cancer incidence has been studied for many years, but the effect of smoking on hormonal therapy has not been previously reported. We investigated the effect of smoking on hormonal therapy by performing in vitro experiments. We first prepared tobacco smoke condensate (TSC) and examined its effect on estrogen receptor (ER) activity. The ER activity was analyzed using MCF-7-E10 cells into which the estrogen-responsive element (ERE)-green fluorescent protein (GFP) reporter gene had been stably introduced (GFP assay) and performing an ERE-luciferase assay. TSC significantly activated ERs, and upregulated its endogenous target genes. This activation was inhibited by fulvestrant but more weakly by tamoxifen. These results suggest that the activation mechanism may be different from that for estrogen. Furthermore, using E10 estrogen depletion-resistant cells (EDR cells) established as a hormonal therapy-resistant model showing estrogen-independent ER activity, ER activation and induction of ER target genes were significantly higher following TSC treatment than by estradiol (E2). These responses were much higher than those of the parental E10 cells. In addition, the phosphorylation status of signaling factors (ERK1/2, Akt) and ER in the E10-EDR cells treated with TSC increased. The gene expression profile induced by estrogenic effects of TSC was characterized by microarray analysis. The findings suggested that TSC activates ER by both ligand-dependent and -independent mechanisms. Although TSC constituents will be metabolized in vivo, breast cancer tissues might be exposed for a long period along with hormonal therapy. Tobacco smoke may have a possibility to interfere with hormonal therapy for breast cancer, which may have important implications for the management of therapy.
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. Electronic address: niwa@med.tohoku.ac.jp.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Shinagawa
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Asari
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Takanobu
authors.affiliation: Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, 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 School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, 980-8575, Japan; Center for Regulatory Epigenome and Diseases, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Hayashi
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke; D013629:Tamoxifen / Q000494:pharmacology; D014026:Nicotiana
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006728:Hormones; D008024:Ligands; D012906:Smoke; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D000077267:Fulvestrant; D004958:Estradiol
keywords: Breast cancer; Estrogen receptor activity; Hormonal therapy resistance; Tobacco smoke