title: Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERα pathway.
abstract: Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Minh Truong
authors.initials: MT
authors.lastname: Do
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Won
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Wonku
authors.initials: W
authors.lastname: Kang
authors.affiliation: Department of Food Science and Culinary, International University of Korea, Jinju, Republic of Korea.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea. Electronic address: taecheon@ynu.ac.kr.
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. Electronic address: hgjeong@cnu.ac.kr.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D002393:Estrogens, Catechol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D061986:MCF-7 Cells; D010766:Phosphorylation; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D002393:Estrogens, Catechol; D020738:Leptin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1
keywords: CYP1B1; ERE; ERα; Leptin