Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells
| Autor: | Darrell W. Brann, Bindu Santhamma, Long Wang, I-Tien Yeh, Joseph K. Agyin, Lu-Zhe Sun, Rajeshwar Rao Tekmal, Abhik Bandyopadhyay, Sujit S. Nair, Rakesh Kumar, Dimple Chakravarty, Francis Y. Lee, Binoj C. Nair, Ratna K. Vadlamudi |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Lung Neoplasms Ovariectomy Blotting Western Estrogen receptor Motility Fluorescent Antibody Technique Mice Nude Breast Neoplasms Enzyme-Linked Immunosorbent Assay Biology Protein Serine-Threonine Kinases Article Metastasis Small hairpin RNA Mice Phosphatidylinositol 3-Kinases Cell Movement Cell Line Tumor medicine Cell Adhesion Animals Humans Immunoprecipitation Neoplasm Invasiveness RNA Messenger Cytoskeleton Cell Proliferation Cell Nucleus Kinase Reverse Transcriptase Polymerase Chain Reaction Liver Neoplasms Cell migration medicine.disease src-Family Kinases Oncology Receptors Estrogen Cytoplasm Cancer research Trans-Activators Female Co-Repressor Proteins Signal Transduction Transcription Factors |
| Zdroj: | Cancer research. 70(10) |
| ISSN: | 1538-7445 |
| Popis: | The molecular basis of breast cancer progression to metastasis and the role of estrogen receptor (ER) signaling in this process remain poorly understood. Emerging evidence suggests that ER participates in extranuclear signaling in addition to genomic functions. Recent studies identified proline-, glutamic acid–, and leucine-rich protein-1 (PELP1) as one of the components of ER signalosome in the cytoplasm. PELP1 expression is deregulated in metastatic breast tumors. We examined the mechanism and significance of ER-PELP1–mediated extranuclear signals in the cytoskeletal remodeling and metastasis. Using estrogen dendrimer conjugate (EDC) that uniquely activate ER extranuclear signaling and by using model cells that stably express PELP1 short hairpin RNA (shRNA), we show that PELP1 is required for optimal activation of ER extranuclear actions. Using a yeast two-hybrid screen, we identified integrin-linked kinase 1 (ILK1) as a novel PELP1-binding protein. Activation of extranuclear signaling by EDC uniquely enhanced E2-mediated ruffles and filopodia-like structures. Using dominant-negative and dominant-active reagents, we found that estrogen-mediated extranuclear signaling promotes cytoskeleton reorganization through the ER-Src-PELP1-phosphoinositide 3-kinase-ILK1 pathway. Using in vitro Boyden chamber assays and in vivo xenograft assays, we found that ER extranuclear actions contribute to cell migration. Collectively, our results suggest that ER extranuclear actions play a role in cell motility/metastasis, establishing for the first time that endogenous PELP1 serves as a critical component of ER extranuclear actions leading to cell motility/invasion and that the ER-Src-PELP1-ILK1 pathway represents a novel therapeutic target for preventing the emergence of ER-positive metastasis. Cancer Res; 70(10); 4092–101. ©2010 AACR. |
| Databáze: | OpenAIRE |
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