Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner

• Published in: Oncogene Vol. 29; no. 20; pp. 2996 - 3009
• Main Authors: Liu, Z-B, Hou, Y-F, Zhu, J, Hu, D-L, Jin, W, Ou, Z-L, Di, G-H, Wu, J, Shen, Z-Z, Shao, Z-M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.05.2010; Nature Publishing Group
• Subjects: 692/699/67/1059/602; 692/699/67/1347; Animals; Apoptosis; Apoptosis - drug effects; Bacterial vaccines; Biological and medical sciences; Blotting, Western; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Care and treatment; Cell activation; Cell Adhesion - drug effects; Cell Biology; Cell cycle; Cell Line, Tumor; Cell physiology; Cell proliferation; Cell Proliferation - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; Cellular signal transduction; Development and progression; Enzyme-Linked Immunosorbent Assay; Epidermal growth factor; Epidermal growth factor receptors; Female; Fimbriae, Bacterial - metabolism; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Genetics; Gynecology. Andrology. Obstetrics; Health aspects; Hemagglutinins; Hemagglutinins - pharmacology; Human Genetics; Humans; Internal Medicine; Kinases; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mammary gland diseases; Mannose; Mannose - metabolism; Medical sciences; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular and cellular biology; Neoplasm Transplantation; Oncology; original-article; Physiological aspects; Pili; Pseudomonas; Pseudomonas aeruginosa - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Rodents; Signal Transduction; Therapeutic targets; Tumor cell lines; Tumorigenesis; Tumors; Xenografts; China; PA-MSHA vaccine; mannose; breast tumor; sugar binding; EGFR; Breast disease; Breast tumor; Breast cancer; Malignant tumor; Metastasis; Carcinogenesis; Mammary gland diseases; Signal transduction; Inhibition; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.70

To identify more therapeutic targets and clarify the detailed mechanisms of Pseudomonas aeruginosa -mannose-sensitive hemagglutinin (PA-MSHA) on breast cancer cells both in vitro and in vivo . PA-MSHA was administered to epidermal growth factor receptor (EGFR)-positive human breast cancer cell lines MDA-MB-231HM and MDA-MB-468 in vitro and to mice bearing tumor xenografts. The mannose cocultured test was used to detect the effect of mannose on PA-MSHA-induced cell proliferation, cell cycle arrest, apoptosis, and EGFR pathway signaling. We found that cells stimulated with PA-MSHA exhibited a downregulation of EGFR signaling. The addition of mannose partially inhibited the PA-MSHA-stimulated cell anti-proliferative effect, cell apoptosis, cell cycle arrest, activation of apoptosis-associated caspases, and even downregulation of the EGFR signaling pathway. In vivo , PA-MSHA treatment significantly suppressed mammary tumorigenesis in xenografts in mice and decreased lung metastasis in MDA-MB-231HM cell-transplanted mice. Tumor sample analyses confirmed inhibition of the EGFR pathway in the PA-MSHA-treated mice. In conclusion, this study showed that the involvement of the mannose-mediated EGFR pathway has a critical function in the preclinical rationale for the development of PA-MSHA for the treatment of human breast cancer. It also suggests the potentially beneficial use of PA-MSHA in adjuvant therapy for breast tumors with EGFR overexpression.