Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73

Autor: Weng Yip Kong, Yuen Chee Yue, Rozita Rosli, Soon Keng Cheong, Irene So, Kai Hung Tiong, Cyril Chung, Choon Hooi Chua, Heng Lungh Choo, Boon Shing Tan, Su Wei Wong, Jae Ying Lim, Sean I. Quah, Chai Yuin Lee, Cindy Fow, Chee-Onn Leong
Rok vydání: 2010
Předmět:
Cancer Research
Tumor suppressor gene
Combination therapy
Blotting
Western
Receptor
Transforming Growth Factor-beta Type I
Apoptosis
Breast Neoplasms
Protein Serine-Threonine Kinases
Biology
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Breast cancer
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
RNA
Messenger
RNA
Small Interfering
skin and connective tissue diseases
PI3K/AKT/mTOR pathway
Cell Proliferation
Sirolimus
Cisplatin
Reverse Transcriptase Polymerase Chain Reaction
TOR Serine-Threonine Kinases
Tumor Suppressor Proteins
NF-kappa B
Nuclear Proteins
Cancer
Drug Synergism
Tumor Protein p73
medicine.disease
DNA-Binding Proteins
Oncology
Carcinoma
Basal Cell
Cancer research
Breast disease
Proto-Oncogene Proteins c-akt
Receptors
Transforming Growth Factor beta
medicine.drug
Zdroj: Breast Cancer Research and Treatment. 128:301-313
ISSN: 1573-7217
0167-6806
DOI: 10.1007/s10549-010-1055-0
Popis: 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.
Databáze: OpenAIRE
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