Tamoxifen-stimulated growth of breast cancer due to p21 loss

Abde M. Abukhdeir, Michele I. Vitolo, Pedram Argani, Angelo Michael Demarzo, 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 journalArticle

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 languageEnglish (US)
Pages (from-to)288-293
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number1
DOIs
StatePublished - Jan 8 2008

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Keywords

  • Drug resistance
  • Estrogen receptor
  • p21 knockout
  • Selective estrogen receptor modulator

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Abukhdeir, A. M., Vitolo, M. I., Argani, P., Demarzo, 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