title: Additive effects of trastuzumab and genistein on human breast cancer cells.
abstract: Soy isoflavone genistein, a tyrosine kinase inhibitor and agonist of estrogen receptor-β (ERβ), is known to have antitumoral properties. Given that ERβ often is coexpressed with HER2 in breast cancer, both functions of genistein might be able to enhance the antitumoral action of trastuzumab. In this in-vitro study, we tested whether combined treatment with genistein and trastuzumab exerts additive effects on breast cancer cells. HER2-overexpressing breast cancer cell lines were treated with genistein alone and in combination with trastuzumab. The effects of this treatment on proliferation and gene expression were analyzed. Treatment with high-dose genistein (10 μmol/l) significantly increased the growth-inhibitory effect of trastuzumab on HER2-overexpressing, ERα/β-positive BT-474 breast cancer cells. Combinatory treatment using lower doses of trastuzumab exerted similar effects as a single treatment with standard doses of this drug. In contrast, this effect was absent in ERα-negative SK-BR-3 cells. Similar results were obtained after cotreatment with the ERβ agonist, 2,3-bis(4-hydroxyphenyl)propionitrile. The growth-inhibitory effect of both drugs was accompanied by an increased expression of the putative tumor suppressor ERβ variant, cx, and their combination further elevated mRNA levels of this receptor. In conclusion, genistein significantly enhanced the antitumoral effect of trastuzumab on BT-474 breast cancer cells in vitro. The relevance of these data particularly for women with HER2-overexpressing and ERα/β-positive breast cancer has to be verified in animal or clinical studies.
authors.affiliation: Department of Obstetrics and Gynecology, University Medical Center Regensburg, Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Lattrich
authors.forename: Julia
authors.initials: J
authors.lastname: Lubig
authors.forename: Anette
authors.initials: A
authors.lastname: Springwald
authors.forename: Regina
authors.initials: R
authors.lastname: Goerse
authors.forename: Olaf
authors.initials: O
authors.lastname: Ortmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Treeck
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018734:Genes, erbB-2; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019833:Genistein; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab