title: Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions.
abstract: Xanthohumol (XN) is a natural anticancer compound that inhibits the proliferation of oestrogen receptor-α (ERα)-positive breast cancer cells. However, the precise mechanism of the antitumour effects of XN on oestrogen (E2)-dependent cell growth, and especially its direct target molecule(s), remain(s) largely unknown. Here, we focus on whether XN directly binds to the tumour suppressor protein prohibitin 2 (PHB2), forming a novel natural antitumour compound targeting the BIG3-PHB2 complex and acting as a pivotal modulator of E2/ERα signalling in breast cancer cells. XN treatment effectively prevented the BIG3-PHB2 interaction, thereby releasing PHB2 to directly bind to both nuclear- and cytoplasmic ERα. This event led to the complete suppression of the E2-signalling pathways and ERα-positive breast cancer cell growth both in vitro and in vivo, but did not suppress the growth of normal mammary epithelial cells. Our findings suggest that XN may be a promising natural compound to suppress the growth of luminal-type breast cancer.
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
authors.forename: Etsu
authors.initials: E
authors.lastname: Tashiro
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
authors.affiliation: Antibiotics Laboratory, RIKEN CSRS, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyoshi
authors.affiliation: Department of Surgery, National Hospital Organization Higashitokushima Medical Center, Tokushima, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Honda
authors.affiliation: Department of Surgery, Tokushima Breast Care Clinic, Tokushima, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Sasa
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Tokushima, Japan.
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D000091402:Prohibitins; D011427:Propiophenones / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595370:ARFGEF3 protein, human; D000972:Antineoplastic Agents, Phytogenic; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005419:Flavonoids; D020662:Guanine Nucleotide Exchange Factors; C000717331:PHB2 protein, human; D000091402:Prohibitins; D011427:Propiophenones; D012097:Repressor Proteins; C104536:xanthohumol