title: Combination of cyclopamine and tamoxifen promotes survival and migration of mcf-7 breast cancer cells--interaction of hedgehog-gli and estrogen receptor signaling pathways.
abstract: Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERα) signaling has a key role in the development of hormone-dependent breast cancer. We aimed to investigate the effects of inhibiting both pathways simultaneously on breast cancer cell survival and the potential interactions between these two signaling pathways. ER-positive MCF-7 cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERα inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and increased migration. We found upregulated Hh-Gli signaling under these conditions and protein profiling revealed increased expression of proteins involved in cell proliferation and migration. Therefore, even though Hh-Gli signaling seems to be a good potential target for breast cancer therapy, caution must be advised, especially when combining therapies. In addition, we also show a potential direct interaction between the Shh protein and ERα in MCF-7 cells. Our data suggest that the Shh protein is able to activate ERα independently of the canonical Hh-Gli signaling pathway. Therefore, this may present an additional boost for ER-positive cells that express Shh, even in the absence of estrogen.
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Sabol
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Diana
authors.initials: D
authors.lastname: Trnski
authors.affiliation: Faculty of Education, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Uzarevic
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Petar
authors.initials: P
authors.lastname: Ozretic
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Musani
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Maja
authors.initials: M
authors.lastname: Rafaj
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Cindric
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Levanat
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000009:adverse effects / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014704:Veratrum Alkaloids / Q000009:adverse effects / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D013629:Tamoxifen; C000541:cyclopamine