Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer

Todd W. Miller, Bryan T. Hennessy, Ana M. González-Angulo, Emily M. Fox, Gordon B. Mills, Heidi Chen, Catherine Higham, Carlos García-Echeverría, Yu Shyr, Carlos L. Arteaga

Research output: Contribution to journalArticle

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Abstract

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.

Original languageEnglish (US)
Pages (from-to)2406-2413
Number of pages8
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

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Phosphatidylinositol 3-Kinase
Estrogen Receptors
Hormones
Phosphatidylinositol 3-Kinases
Estrogens
Breast Neoplasms
Sirolimus
Phosphotransferases
Therapeutics
Neoplasms
Protein Array Analysis
Proteomics
Estradiol
Phosphorylation
Apoptosis
Cell Line
Growth

ASJC Scopus subject areas

  • Medicine(all)

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Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. / Miller, Todd W.; Hennessy, Bryan T.; González-Angulo, Ana M.; Fox, Emily M.; Mills, Gordon B.; Chen, Heidi; Higham, Catherine; García-Echeverría, Carlos; Shyr, Yu; Arteaga, Carlos L.

In: Journal of Clinical Investigation, Vol. 120, No. 7, 01.07.2010, p. 2406-2413.

Research output: Contribution to journalArticle

Miller, TW, Hennessy, BT, González-Angulo, AM, Fox, EM, Mills, GB, Chen, H, Higham, C, García-Echeverría, C, Shyr, Y & Arteaga, CL 2010, 'Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer', Journal of Clinical Investigation, vol. 120, no. 7, pp. 2406-2413. https://doi.org/10.1172/JCI41680
Miller, Todd W. ; Hennessy, Bryan T. ; González-Angulo, Ana M. ; Fox, Emily M. ; Mills, Gordon B. ; Chen, Heidi ; Higham, Catherine ; García-Echeverría, Carlos ; Shyr, Yu ; Arteaga, Carlos L. / Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 7. pp. 2406-2413.
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