Format

Send to

Choose Destination
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.

Author information

1
Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
2
Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
3
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
4
Kazan Federal University, Kazan, Russia.
5
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
6
Biostatistics Center, George Washington University, Washington, DC, USA.

Abstract

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.

PMID:
26165839
PMCID:
PMC4712124
DOI:
10.1038/onc.2015.226
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center