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

• Published in: Oncogene Vol. 35; no. 13; pp. 1643 - 1656
• Main Authors: Zhang, Y-W, Nasto, R E, Varghese, R, Jablonski, S A, Serebriiskii, I G, Surana, R, Calvert, V S, Bebu, I, Murray, J, Jin, L, Johnson, M, Riggins, R, Ressom, H, Petricoin, E, Clarke, R, Golemis, E A, Weiner, L M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-03-2016; Nature Publishing Group
• Subjects: 13/109; 13/31; 13/89; 38/79; 631/154/51/2053; 631/337/505; 631/67/1347; 631/80/304; 82/29; 96/2; AKT protein; Analysis; Apoptosis; Aromatase; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Development and progression; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Estrogen; Estrogen receptors; Estrogens; Estrogens - pharmacology; Female; G1 phase; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic translation; Health aspects; HEK293 Cells; Human Genetics; Humans; Innovations; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MCF-7 Cells; Medicine; Medicine & Public Health; Molecular targeted therapy; mRNA; Oncology; original-article; Protein arrays; Receptors; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; TOR protein; Tumor cell lines; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.226

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.