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

摘要: Resistance to therapies targeting the estrogen pathway remains a challenge in treatment of receptor-positive breast cancer. To address this challenge, systems biology approach was used. A library small interfering RNAs an receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable estrogen-dependent MCF7 cells, but selectively required for survival estrogen-independent MCF7-derived cells multiple additional cancer cell lines. Integration information tumor suppressor gene TOB1 as critical determinant ER-positive survival. Depletion promoted G1 phase arrest sensitivity AKT mammalian target rapmycin (mTOR) inhibitors not cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling significant signaling reprogramming differed estrogen-sensitive estrogen-resistant These data support novel function mediating cancers. studies also provide evidence combining inhibition AKT/mTOR therapeutic strategy, with potential translational significance management patients