Medical College of Wisconsin
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Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010 Jul;120(7):2406-13

Date

06/10/2010

Pubmed ID

20530877

Pubmed Central ID

PMC2898598

DOI

10.1172/JCI41680

Scopus ID

2-s2.0-77954974573 (requires institutional sign-in at Scopus site)   491 Citations

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 17beta-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.

Author List

Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, García-Echeverría C, Shyr Y, Arteaga CL

Author

Todd W. Miller PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Apoptosis
Breast Neoplasms
Estradiol
Estrogen Receptor alpha
Estrogens
Female
Hormones
Humans
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Receptors, Estrogen
Signal Transduction
Sirolimus