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

Miller, Todd W and Hennessy, Bryan T and Gonzalez-Angulo, Ana M and Fox, Emily M and Mills, Gordon B and Ghazoui, Zara and Dowsett, Mitch and Higham, Catherine and Garcia-Echeverria, Carlos and Shyr, Yu and Arteaga, Carlos L (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone-dependence in estrogen receptor-positive breast cancer cells. Journal of clinical investigation, 120 (7). pp. 2406-2413. ISSN 0021-9738

Abstract

A significant fraction of estrogen receptor  (ER)-positive breast cancers exhibits therapeutic resistance to aromatase inhibitors (AIs), which block estrogen biosynthesis. To model acquired AI resistance, we generated hormone-independent derivatives of four ER-positive breast cancer cell lines (termed long-term estrogen-deprived, LTED). LTED cells showed variable changes in ER levels and 17-estradiol sensitivity. Proteomic profiling using 652 antibodies revealed increased phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), an mTOR substrate, in LTED lines compared to parental controls. Activation of the phosphatidylinositol-3 kinase (PI3K)/mTOR pathway was also increased in LTED lines as measured by P-AKT and P-p70S6K immunoblotting. Using receptor tyrosine kinase arrays, we found increased phosphorylation of the receptors for IGF-I (IGF-IR) and/or insulin (InsR) in three LTED lines. Treatment with inhibitors of IGF-IR/InsR, PI3K, or mTOR suppressed LTED cell growth, induced apoptosis, and prevented the emergence of hormone-independent cells. Gene expression microarray analysis identified 102 genes with decreased expression ≥1.5-fold in LTED lines. This 102-gene signature was predictive of early tumor response to neoadjuvant anastrozole therapy in a cohort of 69 hormone receptor-positive breast cancer patients. Finally, we quantified levels of PI3K pathway proteins in homogenates from 64 hormone receptor-positive primary tumors using reverse-phase protein microarrays. Following adjuvant endocrine therapy, patients with tumors bearing high PI3K activity had significantly shorter disease-free survival. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely on PI3K. Thus, acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both the ER and PI3K pathways.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2064

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