Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells

Dimple Chakravarty, Sujit S. Nair, Bindu Santhamma, Binoj C. Nair, Long Wang, Abhik Bandyopadhyay, Joseph K. Agyin, Darrell Brann, Lu Zhe Sun, I. Tien Yeh, Francis Y. Lee, Rajeshwar Rao Tekmal, Rakesh Kumar, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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 cellmigration. 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.

Original languageEnglish (US)
Pages (from-to)4092-4101
Number of pages10
JournalCancer Research
Volume70
Issue number10
DOIs
StatePublished - May 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chakravarty, D., Nair, S. S., Santhamma, B., Nair, B. C., Wang, L., Bandyopadhyay, A., Agyin, J. K., Brann, D., Sun, L. Z., Yeh, I. T., Lee, F. Y., Tekmal, R. R., Kumar, R., & Vadlamudi, R. K. (2010). Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells. Cancer Research, 70(10), 4092-4101. https://doi.org/10.1158/0008-5472.CAN-09-3834