Addition of the Akt inhibitor triciribine overcomes antibody resistance in cells from ErbB2/Neu-positive/PTEN-deficient mammary tumors.

Abstract

Trastuzumab resistance is a challenging problem in ErbB2/HER2-positive breast cancers. Multiple mechanisms of resistance have been proposed and, thus, may require the development of more personalized therapies. In this study, we report the establishment of a mouse mammary cancer cell line, designated MT104T, obtained from spontaneous tumors in genetically engineered FVB/N-ErbB2/Neu-positive-PTEN-deficient mice. The critical molecular phenotype of MT104T cells was confirmed by genotyping and western blot analysis. This cell line was tumorigenic in immunologically intact syngeneic mice, forming tumors of generally similar histology as its origin. PTEN loss led to hyperactivation of Akt and conferred resistance to anti-ErbB2/Neu antibody treatment in MT104T cells. Addition of the Akt inhibitor triciribine (TCN) inhibited the viability of MT104T cells in a dose- and time-dependent manner as evaluated by MTT assay. ErbB2/Neu antibody and TCN combination treatment greatly induced apoptosis of MT104T cells as indicated by Annexin V-FITC staining. Moreover, this combination treatment also significantly reduced both Akt and Erk activities, which are responsible for the inhibitory effect on MT104T cells. Therefore, MT104T cells could represent an alternative model system to investigate the nature of ErbB2‑positive breast cancer and for the experimental therapeutics studies of this disease. Our findings also suggest that combination of TCN may be a potential strategy for the treatment of trastu-zumab-resistant breast cancer mediated by PTEN loss or PI3K hyperactivation, which may facilitate the development of more personalized therapies for breast cancer patients.

• Authors: Qingfei Wang, Hui Ding, Baorui Liu, Shau-Hsuan Li, Ping Li, Hailiang Ge, Kui Zhang
• Journal: International journal of oncology (Int J Oncol) Vol. 44 Issue 4 Pg. 1277-83 (Apr 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 24452693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Ribonucleosides
• triciribine
• Phosphatidylinositol 3-Kinases
• Erbb2 protein, mouse
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Pten protein, mouse
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Female
• Mammary Neoplasms, Animal (drug therapy, immunology)
• Mice
• Mice, Knockout
• PTEN Phosphohydrolase (genetics)
• Phosphatidylinositol 3-Kinases (biosynthesis)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Receptor, ErbB-2 (genetics, immunology)
• Ribonucleosides (pharmacology)
• Trastuzumab