title: Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73.
abstract: Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.
authors.affiliation: School of Pharmacy and Health Sciences, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Su Wei
authors.initials: SW
authors.lastname: Wong
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.forename: Weng Yip
authors.initials: WY
authors.lastname: Kong
authors.forename: Yuen Chee
authors.initials: YC
authors.lastname: Yue
authors.forename: Choon Hooi
authors.initials: CH
authors.lastname: Chua
authors.forename: Jae Ying
authors.initials: JY
authors.lastname: Lim
authors.forename: Chai Yuin
authors.initials: CY
authors.lastname: Lee
authors.forename: Sean I
authors.initials: SI
authors.lastname: Quah
authors.forename: Cindy
authors.initials: C
authors.lastname: Fow
authors.forename: Cyril
authors.initials: C
authors.lastname: Chung
authors.forename: Irene
authors.initials: I
authors.lastname: So
authors.forename: Boon Shing
authors.initials: BS
authors.lastname: Tan
authors.forename: Heng Lungh
authors.initials: HL
authors.lastname: Choo
authors.forename: Rozita
authors.initials: R
authors.lastname: Rosli
authors.forename: Soon-Keng
authors.initials: SK
authors.lastname: Cheong
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002945:Cisplatin; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C000606460:TP73 protein, human; C546842:MTOR protein, human