Tamoxifen-stimulated growth of breast cancer due to p21 loss

Abde M. Abukhdeir; Michele I. Vitolo; Pedram Argani; Angelo M. De Marzo; Bedri Karakas; Hiroyuki Konishi; John P. Gustin; Josh Lauring; Joseph P. Garay; Courtney Pendleton; Yuko Konishi; Brian G. Blair; Keith Brenner; Elizabeth Garrett-Mayer; Hetty Carraway; Kurtis E. Bachman; Ho Park Ben

doi:10.1073/pnas.0710887105

Tamoxifen-stimulated growth of breast cancer due to p21 loss

Abde M. Abukhdeir, Michele I. Vitolo, Pedram Argani, Angelo M. De Marzo, Bedri Karakas, Hiroyuki Konishi, John P. Gustin, Josh Lauring, Joseph P. Garay, Courtney Pendleton, Yuko Konishi, Brian G. Blair, Keith Brenner, Elizabeth Garrett-Mayer, Hetty Carraway, Kurtis E. Bachman, Ho Park Ben

Research output: Contribution to journal › Article › peer-review

69 Scopus citations

Abstract

Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.

Original language	English (US)
Pages (from-to)	288-293
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	105
Issue number	1
DOIs	https://doi.org/10.1073/pnas.0710887105
State	Published - Jan 8 2008

Keywords

Drug resistance
Estrogen receptor
Selective estrogen receptor modulator
p21 knockout

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.0710887105

Cite this

Abukhdeir, A. M., Vitolo, M. I., Argani, P., De Marzo, A. M., Karakas, B., Konishi, H., Gustin, J. P., Lauring, J., Garay, J. P., Pendleton, C., Konishi, Y., Blair, B. G., Brenner, K., Garrett-Mayer, E., Carraway, H., Bachman, K. E., & Ben, H. P. (2008). Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proceedings of the National Academy of Sciences of the United States of America, 105(1), 288-293. https://doi.org/10.1073/pnas.0710887105

Abukhdeir, AM, Vitolo, MI, Argani, P , De Marzo, AM, Karakas, B, Konishi, H, Gustin, JP, Lauring, J, Garay, JP, Pendleton, C, Konishi, Y, Blair, BG, Brenner, K, Garrett-Mayer, E, Carraway, H, Bachman, KE & Ben, HP 2008, 'Tamoxifen-stimulated growth of breast cancer due to p21 loss', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 1, pp. 288-293. https://doi.org/10.1073/pnas.0710887105

@article{8281d4d698e84a73a82c44370d4ba90c,

title = "Tamoxifen-stimulated growth of breast cancer due to p21 loss",

abstract = "Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.",

keywords = "Drug resistance, Estrogen receptor, Selective estrogen receptor modulator, p21 knockout",

author = "Abukhdeir, {Abde M.} and Vitolo, {Michele I.} and Pedram Argani and {De Marzo}, {Angelo M.} and Bedri Karakas and Hiroyuki Konishi and Gustin, {John P.} and Josh Lauring and Garay, {Joseph P.} and Courtney Pendleton and Yuko Konishi and Blair, {Brian G.} and Keith Brenner and Elizabeth Garrett-Mayer and Hetty Carraway and Bachman, {Kurtis E.} and Ben, {Ho Park}",

year = "2008",

month = jan,

day = "8",

doi = "10.1073/pnas.0710887105",

language = "English (US)",

volume = "105",

pages = "288--293",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "1",

}

TY - JOUR

T1 - Tamoxifen-stimulated growth of breast cancer due to p21 loss

AU - Abukhdeir, Abde M.

AU - Vitolo, Michele I.

AU - Argani, Pedram

AU - De Marzo, Angelo M.

AU - Karakas, Bedri

AU - Konishi, Hiroyuki

AU - Gustin, John P.

AU - Lauring, Josh

AU - Garay, Joseph P.

AU - Pendleton, Courtney

AU - Konishi, Yuko

AU - Blair, Brian G.

AU - Brenner, Keith

AU - Garrett-Mayer, Elizabeth

AU - Carraway, Hetty

AU - Bachman, Kurtis E.

AU - Ben, Ho Park

PY - 2008/1/8

Y1 - 2008/1/8

N2 - Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.

AB - Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.

KW - Drug resistance

KW - Estrogen receptor

KW - Selective estrogen receptor modulator

KW - p21 knockout

UR - http://www.scopus.com/inward/record.url?scp=38349137676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38349137676&partnerID=8YFLogxK

U2 - 10.1073/pnas.0710887105

DO - 10.1073/pnas.0710887105

M3 - Article

C2 - 18162533

AN - SCOPUS:38349137676

SN - 0027-8424

VL - 105

SP - 288

EP - 293

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 1

ER -

Tamoxifen-stimulated growth of breast cancer due to p21 loss

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this