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Increased erbB3 promotes erbB2/neu-driven mammary tumor proliferation and co-targeting of erbB2/erbB3 receptors exhibits potent inhibitory effects on breast cancer cells.
- Source :
-
International journal of clinical and experimental pathology [Int J Clin Exp Pathol] 2015 Jun 01; Vol. 8 (6), pp. 6143-56. Date of Electronic Publication: 2015 Jun 01 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- The kinase deficient erbB3 receptor frequently co-expresses and interacts with erbB2 in human breast cancer to activate the oncogenic signaling pathways, and thus promote breast cancer cell survival/proliferation. In the current study, we discovered that the expression of endogenous mouse erbB3 was increased in the mammary tumors-derived from wild type (wt) rat erbB2/neu-transgenic mice, and the co-expression of erbB2 and erbB3 significantly promoted mammary tumor proliferation in vivo. Co-immunoprecipitation assays detected a heterodimeric complex consisting of the transgene encoded protein rat erbB2 and the endogenous mouse erbB3 in the mammary tumors. Specific knockdown of mouse erbB3 dramatically inhibited proliferation of the mammary tumor cell lines-derived from the transgenic mice. Elevated expression of erbB3 protein, but not mRNA, was abserved in human breast cancer cells upon ectopic expression of erbB2. Additional studies revealed that overexpression of erbB2 downregulated three erbB3-targeting miRNAs, miR-125a, miR-125b, and miR-205, whereas the erbB2 kinase inhibitor (lapatinib) significantly enhanced expression of the three miRNAs in breast cancer cells, suggesting that erbB2 might regulate erbB3 expression through a miRNA-dependent mechanism. Furthermore, an anti-erbB3 monoclonal IgG1 antibody (Ab) in combination with Herceptin mainly inactivated Akt and significantly inhibited proliferation of erbB2-overexpressing breast cancer cells. Collectively, our data indicate that increased expression of erbB3 plays a pivotal role in activating downstream PI-3K/Akt pathway and promoting erbB2-driven mammary/breast tumorigenesis. Simultaneous targeting of erbB2 and erbB3 with two IgG1 Abs may be an effective strategy to treat breast cancer patients whose tumors overexpress both erbB2 and erbB3.
- Subjects :
- Animals
Breast Neoplasms enzymology
Breast Neoplasms genetics
Breast Neoplasms pathology
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Lapatinib
MCF-7 Cells
Mice
Mice, Transgenic
MicroRNAs genetics
MicroRNAs metabolism
Molecular Targeted Therapy
Phosphatidylinositol 3-Kinase metabolism
Proto-Oncogene Proteins c-akt metabolism
RNA Interference
Receptor, ErbB-2 genetics
Receptor, ErbB-2 metabolism
Receptor, ErbB-3 genetics
Receptor, ErbB-3 metabolism
Signal Transduction drug effects
Time Factors
Transfection
Tumor Burden drug effects
Antineoplastic Combined Chemotherapy Protocols pharmacology
Breast Neoplasms drug therapy
Cell Proliferation drug effects
Protein Kinase Inhibitors pharmacology
Quinazolines pharmacology
Receptor, ErbB-2 antagonists & inhibitors
Receptor, ErbB-3 antagonists & inhibitors
Trastuzumab pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1936-2625
- Volume :
- 8
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- International journal of clinical and experimental pathology
- Publication Type :
- Academic Journal
- Accession number :
- 26261492