Chemotherapy resistance of mouse WAP-SVT t breast cancer cells is mediated by osteopontin, inhibiting apoptosis downstream of caspase-3

• Published in: Oncogene Vol. 26; no. 20; pp. 2840 - 2850
• Main Authors: GRAESSMANN, M, BERG, B, FUCHS, B, KLEIN, A, GRAESSMANN, A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 03.05.2007; Nature Publishing Group
• Subjects: Ageing, cell death; AKT protein; Animals; Antibiotics, Antineoplastic - pharmacology; Antigens, Polyomavirus Transforming - genetics; Antitumor agents; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Breast cancer; C cells; Cancer cells; Care and treatment; Caspase 3 - physiology; Caspase-3; Caspase-9; Cell activation; Cell death; Cell physiology; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemoresistance; Chemotherapy; Culture Media, Serum-Free - pharmacology; Cytochrome; Cytochrome c; Cytochromes c - metabolism; DNA microarrays; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Glycoproteins; Gynecology. Andrology. Obstetrics; Health aspects; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Mammary gland diseases; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - pathology; Mammary Neoplasms, Animal - secretion; MAP kinase; Medical sciences; Mice; Mice, Transgenic; Milk Proteins - genetics; Missense mutation; Mitochondria; Mitochondria - metabolism; Models, Biological; Molecular and cellular biology; Oncology; Osteopontin; Osteopontin - physiology; Osteopontin - secretion; p53 Protein; Protein kinase; Transgenic animals; Tumor Cells, Cultured; Tumors; Germany; breast cancer cells; Enzyme; inhibition of apoptosis; Rodentia; Caspase; Osteopontin; Breast cancer; Malignant tumor; Microarray; Carcinogenesis; therapy resistance; Resistance; Mammary gland diseases; Peptidases; Vertebrata; Chemotherapy; Mammalia; Mouse; T-Lymphocyte; Hydrolases; Inhibition; Apoptosis; caspase-3
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210096

Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.