title: The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer.
abstract: Around 70% of breast cancers express the estrogen receptor α (ERα) and depend on estrogen for growth, survival and disease progression. The presence of hormone sensitivity is usually associated with a favorable prognosis. Use of adjuvant anti-endocrine therapy has significantly decreased breast cancer mortality in patients with early-stage disease, and anti-endocrine therapy also plays a central role in the treatment of advanced stages. However a subset of hormone receptor-positive breast cancers do not benefit from anti-endocrine therapy, and nearly all hormone receptor-positive metastatic breast cancers ultimately develop resistance to anti-hormonal therapies. Despite new insights into mechanisms of anti-endocrine therapy resistance, e.g., crosstalk between ERα and Her2/neu, the management of advanced hormone-receptor-positive breast cancers that are resistant to anti-endocrine agents remains a significant challenge. In the present study, we demonstrate that the proteasome inhibitor Bortezomib strongly inhibits ERα and HER2/neu expression, increases expression of cyclin-dependent kinase inhibitors, inhibits expression of multiple genes associated with poor prognosis in ERα+ breast cancer patients and induces cell death in ER+ breast cancer cells in both the presence and absence of functional p53. Although Bortezomib increased the levels of p53 and increased the expression of pro-apoptotic target genes in ERα+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERα+ breast cancer cells through suppression of ERα expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53. These findings suggest that Bortezomib might have the potential to improve the management of anti-endocrine therapy resistant ERα+ breast cancers independently of their p53 status.
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Thaler
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Gitta
authors.initials: G
authors.lastname: Thiede
authors.affiliation: IfADo-Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of Pathology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.affiliation: Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Centre for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|KIT Campus Nord, Institute for Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C506487:ESR1 protein, human
keywords: Her2 inhibition; estrogen receptor alpha inhibition; proteasome inhibition