Aromatase inhibitor resistance mechanism identified in breast cancer
MedWire News: Phosphatidylinositol-3 kinase (PI3K) plays a key role in the emergence and maintenance of resistance to aromatase inhibitors (AIs) in breast cancer, US research shows.
“Many breast cancers exhibit a degree of dependence on estrogen for tumor growth,” note Carlos Arteaga (Vanderbilt University Medical Center, Nashville, Tennessee) and colleagues.
“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,” they add.
To define mechanisms underlying the development of resistance to endocrine therapies including AIs, Arteaga and team analyzed molecular changes in four human breast cancer cell lines subject to long-term estrogen deprivation (LTED), a condition that mimics an endocrine therapy regimen.
The researchers report that the LTED cells showed variable changes in estrogen receptor (ER) levels and sensitivity to 17β-estradiol.
Proteomic profiling of the 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.
Furthermore, inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells.
In support of these findings, the researchers identified a protein signature of PI3K pathway activation using reverse-phase protein microarrays. The signature was predictive for poor disease outcome following adjuvant endocrine therapy in breast cancer patients.
“Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling,” conclude Arteaga and co-authors in the Journal of Clinical Investigation.
They add that their findings also imply that “acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.”
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By Laura Dean