Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo

Careen K. Tang, Xiao Zheng Wu Concepcion, Melissa Milan, Xiaoqi Gong, Elizabeth Montgomery, Marc E Lippman

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

ErbB-4 is a recently discovered member of the class I receptor tyrosine kinase family (ErbB). Little is known about its expression and its importance in human malignancy. To delineate the biological function of ErbB-4 receptors in breast cancer, we used a hammerhead ribozyme strategy to achieve down- regulation of ErbB-4 receptors in various breast cancer cell lines. We observed that down-regulation of ErbB-4 in estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and T47D), which express relatively high levels of ErbB-4, significantly inhibited colony formation. No effects were observed in estrogen receptor-negative (ER-) MDA-MB-453 cells, which express low levels of endogenous ErbB4 and high levels of ErbB-2 and ErbB-3. This occurred despite the fact that fluorescence-activated cell sorter analysis of these latter cells revealed that the expression of the ErbB-4 receptor was completely abrogated by ribozyme treatment. Furthermore, down- regulation of ErbB-4 in T47D and MCF-7 cells significantly inhibited tumor formation in athymic nude mice (P < 0.03 and P < 0.001, respectively). In addition, NRG-stimulated phosphorylation of ErbB-4- and NRG-induced colony formation was significantly reduced in ribozyme-transfected T47D cells. These data provide the first evidence that elevation of ErbB-4 expression plays a role in the proliferation of some ER+ human breast cancer cell lines (T47D and MCF-7) that express high levels of ErbB-4. We have also investigated the expression of ErbB-4 in human primary breast carcinoma specimens, using immunohistochemical staining with an anti-ErbB-4 monoclonal antibody. ErbB-4 expression was found in 60% of the 50 primary breast tumors examined, and high intense immunoreactivity of ErbB-4 was detected in 18% of these primary breast tumors. ErbB-4 receptor expression appeared to correlate with ER+ primary breast tumors. A similar correlation was also observed in the human breast cancer cell lines. These results provide a better understanding of the biological significance of ErbB-4 receptor in breast cancer. Our data suggest that elevation of the ErbB-4 receptor plays a role in ER+ breast cancer cell proliferation. Moreover, ribozyme technology provides a useful tool to delineate the role of a particular gene product.

Original languageEnglish
Pages (from-to)5315-5322
Number of pages8
JournalCancer Research
Volume59
Issue number20
StatePublished - Oct 15 1999
Externally publishedYes

Fingerprint

Catalytic RNA
Estrogen Receptors
Down-Regulation
Cell Proliferation
Breast Neoplasms
Cell Line
Nude Mice
In Vitro Techniques
MCF-7 Cells
Receptor Protein-Tyrosine Kinases
ErbB-4 Receptor
Neoplasms
Fluorescence
Monoclonal Antibodies
Phosphorylation
Staining and Labeling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tang, C. K., Concepcion, X. Z. W., Milan, M., Gong, X., Montgomery, E., & Lippman, M. E. (1999). Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo. Cancer Research, 59(20), 5315-5322.

Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo. / Tang, Careen K.; Concepcion, Xiao Zheng Wu; Milan, Melissa; Gong, Xiaoqi; Montgomery, Elizabeth; Lippman, Marc E.

In: Cancer Research, Vol. 59, No. 20, 15.10.1999, p. 5315-5322.

Research output: Contribution to journalArticle

Tang, CK, Concepcion, XZW, Milan, M, Gong, X, Montgomery, E & Lippman, ME 1999, 'Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo', Cancer Research, vol. 59, no. 20, pp. 5315-5322.
Tang, Careen K. ; Concepcion, Xiao Zheng Wu ; Milan, Melissa ; Gong, Xiaoqi ; Montgomery, Elizabeth ; Lippman, Marc E. / Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo. In: Cancer Research. 1999 ; Vol. 59, No. 20. pp. 5315-5322.
@article{6e11ea92057948aaafdb58e82e4ffee7,
title = "Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo",
abstract = "ErbB-4 is a recently discovered member of the class I receptor tyrosine kinase family (ErbB). Little is known about its expression and its importance in human malignancy. To delineate the biological function of ErbB-4 receptors in breast cancer, we used a hammerhead ribozyme strategy to achieve down- regulation of ErbB-4 receptors in various breast cancer cell lines. We observed that down-regulation of ErbB-4 in estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and T47D), which express relatively high levels of ErbB-4, significantly inhibited colony formation. No effects were observed in estrogen receptor-negative (ER-) MDA-MB-453 cells, which express low levels of endogenous ErbB4 and high levels of ErbB-2 and ErbB-3. This occurred despite the fact that fluorescence-activated cell sorter analysis of these latter cells revealed that the expression of the ErbB-4 receptor was completely abrogated by ribozyme treatment. Furthermore, down- regulation of ErbB-4 in T47D and MCF-7 cells significantly inhibited tumor formation in athymic nude mice (P < 0.03 and P < 0.001, respectively). In addition, NRG-stimulated phosphorylation of ErbB-4- and NRG-induced colony formation was significantly reduced in ribozyme-transfected T47D cells. These data provide the first evidence that elevation of ErbB-4 expression plays a role in the proliferation of some ER+ human breast cancer cell lines (T47D and MCF-7) that express high levels of ErbB-4. We have also investigated the expression of ErbB-4 in human primary breast carcinoma specimens, using immunohistochemical staining with an anti-ErbB-4 monoclonal antibody. ErbB-4 expression was found in 60{\%} of the 50 primary breast tumors examined, and high intense immunoreactivity of ErbB-4 was detected in 18{\%} of these primary breast tumors. ErbB-4 receptor expression appeared to correlate with ER+ primary breast tumors. A similar correlation was also observed in the human breast cancer cell lines. These results provide a better understanding of the biological significance of ErbB-4 receptor in breast cancer. Our data suggest that elevation of the ErbB-4 receptor plays a role in ER+ breast cancer cell proliferation. Moreover, ribozyme technology provides a useful tool to delineate the role of a particular gene product.",
author = "Tang, {Careen K.} and Concepcion, {Xiao Zheng Wu} and Melissa Milan and Xiaoqi Gong and Elizabeth Montgomery and Lippman, {Marc E}",
year = "1999",
month = "10",
day = "15",
language = "English",
volume = "59",
pages = "5315--5322",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "20",

}

TY - JOUR

T1 - Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor- positive breast cancer cells inhibits proliferation both in vitro and in vivo

AU - Tang, Careen K.

AU - Concepcion, Xiao Zheng Wu

AU - Milan, Melissa

AU - Gong, Xiaoqi

AU - Montgomery, Elizabeth

AU - Lippman, Marc E

PY - 1999/10/15

Y1 - 1999/10/15

N2 - ErbB-4 is a recently discovered member of the class I receptor tyrosine kinase family (ErbB). Little is known about its expression and its importance in human malignancy. To delineate the biological function of ErbB-4 receptors in breast cancer, we used a hammerhead ribozyme strategy to achieve down- regulation of ErbB-4 receptors in various breast cancer cell lines. We observed that down-regulation of ErbB-4 in estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and T47D), which express relatively high levels of ErbB-4, significantly inhibited colony formation. No effects were observed in estrogen receptor-negative (ER-) MDA-MB-453 cells, which express low levels of endogenous ErbB4 and high levels of ErbB-2 and ErbB-3. This occurred despite the fact that fluorescence-activated cell sorter analysis of these latter cells revealed that the expression of the ErbB-4 receptor was completely abrogated by ribozyme treatment. Furthermore, down- regulation of ErbB-4 in T47D and MCF-7 cells significantly inhibited tumor formation in athymic nude mice (P < 0.03 and P < 0.001, respectively). In addition, NRG-stimulated phosphorylation of ErbB-4- and NRG-induced colony formation was significantly reduced in ribozyme-transfected T47D cells. These data provide the first evidence that elevation of ErbB-4 expression plays a role in the proliferation of some ER+ human breast cancer cell lines (T47D and MCF-7) that express high levels of ErbB-4. We have also investigated the expression of ErbB-4 in human primary breast carcinoma specimens, using immunohistochemical staining with an anti-ErbB-4 monoclonal antibody. ErbB-4 expression was found in 60% of the 50 primary breast tumors examined, and high intense immunoreactivity of ErbB-4 was detected in 18% of these primary breast tumors. ErbB-4 receptor expression appeared to correlate with ER+ primary breast tumors. A similar correlation was also observed in the human breast cancer cell lines. These results provide a better understanding of the biological significance of ErbB-4 receptor in breast cancer. Our data suggest that elevation of the ErbB-4 receptor plays a role in ER+ breast cancer cell proliferation. Moreover, ribozyme technology provides a useful tool to delineate the role of a particular gene product.

AB - ErbB-4 is a recently discovered member of the class I receptor tyrosine kinase family (ErbB). Little is known about its expression and its importance in human malignancy. To delineate the biological function of ErbB-4 receptors in breast cancer, we used a hammerhead ribozyme strategy to achieve down- regulation of ErbB-4 receptors in various breast cancer cell lines. We observed that down-regulation of ErbB-4 in estrogen receptor-positive (ER+) human breast cancer cell lines (MCF-7 and T47D), which express relatively high levels of ErbB-4, significantly inhibited colony formation. No effects were observed in estrogen receptor-negative (ER-) MDA-MB-453 cells, which express low levels of endogenous ErbB4 and high levels of ErbB-2 and ErbB-3. This occurred despite the fact that fluorescence-activated cell sorter analysis of these latter cells revealed that the expression of the ErbB-4 receptor was completely abrogated by ribozyme treatment. Furthermore, down- regulation of ErbB-4 in T47D and MCF-7 cells significantly inhibited tumor formation in athymic nude mice (P < 0.03 and P < 0.001, respectively). In addition, NRG-stimulated phosphorylation of ErbB-4- and NRG-induced colony formation was significantly reduced in ribozyme-transfected T47D cells. These data provide the first evidence that elevation of ErbB-4 expression plays a role in the proliferation of some ER+ human breast cancer cell lines (T47D and MCF-7) that express high levels of ErbB-4. We have also investigated the expression of ErbB-4 in human primary breast carcinoma specimens, using immunohistochemical staining with an anti-ErbB-4 monoclonal antibody. ErbB-4 expression was found in 60% of the 50 primary breast tumors examined, and high intense immunoreactivity of ErbB-4 was detected in 18% of these primary breast tumors. ErbB-4 receptor expression appeared to correlate with ER+ primary breast tumors. A similar correlation was also observed in the human breast cancer cell lines. These results provide a better understanding of the biological significance of ErbB-4 receptor in breast cancer. Our data suggest that elevation of the ErbB-4 receptor plays a role in ER+ breast cancer cell proliferation. Moreover, ribozyme technology provides a useful tool to delineate the role of a particular gene product.

UR - http://www.scopus.com/inward/record.url?scp=0032718015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032718015&partnerID=8YFLogxK

M3 - Article

C2 - 10537315

AN - SCOPUS:0032718015

VL - 59

SP - 5315

EP - 5322

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 20

ER -