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Endocrinology

Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer

Todd W. Miller, Marianela Pérez-Torres, Archana Narasanna, Marta Guix, Olle Stål, Gizeh Pérez-Tenorio, Ana M. Gonzalez-Angulo, Bryan T. Hennessy, Gordon B. Mills, J. Phillip Kennedy, Craig W. Lindsley and Carlos L. Arteaga
Todd W. Miller
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Marianela Pérez-Torres
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Archana Narasanna
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Marta Guix
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Olle Stål
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Gizeh Pérez-Tenorio
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Ana M. Gonzalez-Angulo
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Bryan T. Hennessy
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Gordon B. Mills
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J. Phillip Kennedy
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Craig W. Lindsley
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Carlos L. Arteaga
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DOI: 10.1158/0008-5472.CAN-09-0042 Published May 2009
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Abstract

Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced ER transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating PTEN in the modulation of signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells, suggesting that cotargeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers. [Cancer Res 2009;69(10):4192–201]

  • PTEN
  • antiestrogen
  • breast cancer
  • IGF-IR
  • ErbB3

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received January 13, 2009.
  • Revision received March 20, 2009.
  • Accepted March 23, 2009.
  • ©2009 American Association for Cancer Research.
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Cancer Research: 69 (10)
May 2009
Volume 69, Issue 10
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Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer
Todd W. Miller, Marianela Pérez-Torres, Archana Narasanna, Marta Guix, Olle Stål, Gizeh Pérez-Tenorio, Ana M. Gonzalez-Angulo, Bryan T. Hennessy, Gordon B. Mills, J. Phillip Kennedy, Craig W. Lindsley and Carlos L. Arteaga
Cancer Res May 15 2009 (69) (10) 4192-4201; DOI: 10.1158/0008-5472.CAN-09-0042

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Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer
Todd W. Miller, Marianela Pérez-Torres, Archana Narasanna, Marta Guix, Olle Stål, Gizeh Pérez-Tenorio, Ana M. Gonzalez-Angulo, Bryan T. Hennessy, Gordon B. Mills, J. Phillip Kennedy, Craig W. Lindsley and Carlos L. Arteaga
Cancer Res May 15 2009 (69) (10) 4192-4201; DOI: 10.1158/0008-5472.CAN-09-0042
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