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Oncogene. 2016 Mar 31;35(13):1643-56. doi: 10.1038/onc.2015.226. Epub 2015 Jul 13.

Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.

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Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
Kazan Federal University, Kazan, Russia.
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Biostatistics Center, George Washington University, Washington, DC, USA.


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.

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