Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen [Medical Sciences]
Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silen...

MGMT Inhibition Restores ERα Functional Sensitivity to Anti-Estrogen Therapy.
Authors: Bobustuc GC, Smith JS, Maddipatla S, Jeudy S, Limaye A, Isley B, Caparas ML, Constantino SM, Shah N, Baker CH, Srivenugopal KS, Baidas S, Konduri SD Abstract Anti-estrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We found significant elevation in MGMT expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O(6)-benzylguanine (BG), at non-toxic doses, leads to restoration of a favorable ERα phosphorylation phenotype (high p-ERα Ser167/low pERα Ser118) which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also sh...div id=medwormpbiMedWorm Message:/i/b Please support the a href=http://www.doctorsinchains.org/ target=_blankDoctors In Chains/a campaign for the a href=http://www.doctorsinchains.org/medics/a tortured and sentenced for up to 15 years in a href=http://www.doctorsinchains.org/Bahrain/a. a href=https://twitter.com/#!/search/%23FreeDoctors#FreeDoctors/a/p/div