Tamoxifen-stimulated growth of breast cancer due to p21 loss

被引：75

作者：

Abukhdeir, Abde M. ^{[1
]}

Vitolol, Michele I. ^{[3
]}

Argani, Pedram ^{[1
]}

De Marzo, Angelo M. ^{[1
]}

Karakas, Bedri ^{[1
]}

Konishi, Hiroyuki ^{[1
]}

Gustin, John P. ^{[2
]}

Lauring, Josh ^{[1
]}

Garay, Joseph P. ^{[1
]}

Pendleton, Courtney ^{[1
]}

Konishi, Yuko ^{[1
]}

Blair, Brian G. ^{[1
]}

Brenner, Keith ^{[1
]}

Garrett-Mayer, Elizabeth ^{[4
]}

Carraway, Hetty ^{[1
]}

Bachman, Kurtis E. ^{[3
]}

Park, Ben Ho ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA

[3] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA

[4] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 01期

关键词：

estrogen receptor; p21; knockout; drug resistance; selective estrogen receptor modulator;

D O I：

10.1073/pnas.0710887105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

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-alpha, 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.

引用

页码：288 / 293

页数：6

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