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

64 Citations (Scopus)

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

Fingerprint

Estrogen Receptors
Breast Neoplasms
Neoplasm Metastasis
Dendrimers
Estrogens
Cell Movement
human PELP1 protein
Pseudopodia
1-Phosphatidylinositol 4-Kinase
Cytoskeleton
Heterografts
Protein Binding
Small Interfering RNA
Carrier Proteins
Cytoplasm
Yeasts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chakravarty, D., Nair, S. S., Santhamma, B., Nair, B. C., Wang, L., Bandyopadhyay, A., ... 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

Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells. / Chakravarty, Dimple; Nair, Sujit S.; Santhamma, Bindu; Nair, Binoj C.; Wang, Long; Bandyopadhyay, Abhik; Agyin, Joseph K.; Brann, Darrell; Sun, Lu Zhe; Yeh, I. Tien; Lee, Francis Y.; Tekmal, Rajeshwar Rao; Kumar, Rakesh; Vadlamudi, Ratna K.

In: Cancer Research, Vol. 70, No. 10, 15.05.2010, p. 4092-4101.

Research output: Contribution to journalArticle

Chakravarty, D, Nair, SS, Santhamma, B, Nair, BC, Wang, L, Bandyopadhyay, A, Agyin, JK, Brann, D, Sun, LZ, Yeh, IT, Lee, FY, Tekmal, RR, Kumar, R & Vadlamudi, RK 2010, 'Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells', Cancer Research, vol. 70, no. 10, pp. 4092-4101. https://doi.org/10.1158/0008-5472.CAN-09-3834
Chakravarty D, Nair SS, Santhamma B, Nair BC, Wang L, Bandyopadhyay A et al. Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells. Cancer Research. 2010 May 15;70(10):4092-4101. https://doi.org/10.1158/0008-5472.CAN-09-3834
Chakravarty, Dimple ; Nair, Sujit S. ; Santhamma, Bindu ; Nair, Binoj C. ; Wang, Long ; Bandyopadhyay, Abhik ; Agyin, Joseph K. ; Brann, Darrell ; Sun, Lu Zhe ; Yeh, I. Tien ; Lee, Francis Y. ; Tekmal, Rajeshwar Rao ; Kumar, Rakesh ; Vadlamudi, Ratna K. / Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells. In: Cancer Research. 2010 ; Vol. 70, No. 10. pp. 4092-4101.
@article{d15066389865499085a7f4ddcf10f37f,
title = "Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells",
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.",
author = "Dimple Chakravarty and Nair, {Sujit S.} and Bindu Santhamma and Nair, {Binoj C.} and Long Wang and Abhik Bandyopadhyay and Agyin, {Joseph K.} and Darrell Brann and Sun, {Lu Zhe} and Yeh, {I. Tien} and Lee, {Francis Y.} and Tekmal, {Rajeshwar Rao} and Rakesh Kumar and Vadlamudi, {Ratna K.}",
year = "2010",
month = "5",
day = "15",
doi = "10.1158/0008-5472.CAN-09-3834",
language = "English (US)",
volume = "70",
pages = "4092--4101",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells

AU - Chakravarty, Dimple

AU - Nair, Sujit S.

AU - Santhamma, Bindu

AU - Nair, Binoj C.

AU - Wang, Long

AU - Bandyopadhyay, Abhik

AU - Agyin, Joseph K.

AU - Brann, Darrell

AU - Sun, Lu Zhe

AU - Yeh, I. Tien

AU - Lee, Francis Y.

AU - Tekmal, Rajeshwar Rao

AU - Kumar, Rakesh

AU - Vadlamudi, Ratna K.

PY - 2010/5/15

Y1 - 2010/5/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77952823885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952823885&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-3834

DO - 10.1158/0008-5472.CAN-09-3834

M3 - Article

C2 - 20460518

AN - SCOPUS:77952823885

VL - 70

SP - 4092

EP - 4101

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 10

ER -