Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)-and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.
Bibliographical noteFunding Information:
We are grateful to the Flow Cytometry and Cell Sorting Shared Resource at the Lombardi Comprehensive Cancer Center, which is partially supported by NIH/NCI grant P30-CA051008. We also thank Wei Xu, Alan Zwart, David Goldstein, Annie Zuo and Yuri Gusev for their technical assistance. This study was supported by R01CA050633, CA51880, U54 CA149147 (to LMW), R01CA63366 and R21CA181287 (to EAG), and by the subsidy of the Russian Government to support the program of competitive growth of Kazan Federal University (to IS).
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