Functional Gene Profiling IDs Breast CA Therapeutic Targets

Potential PTEN-mutated and ER-positive breast cancer treatment targets identified

TUESDAY, Aug. 2 (HealthDay News) -- The large-scale functional profiling of genes validates established targets for breast cancer therapy and identifies potential new therapeutic targets, including those for PTEN-mutated and estrogen receptor (ER)-positive breast cancers, according to a study published online Aug. 2 in Cancer Discovery.

Rachel Brough, Ph.D., from the Institute of Cancer Research in the United Kingdom, and colleagues identified genes critical to the growth of specific breast cancer subtypes. A functional screening profile was generated by high-throughput RNA interference in more than 30 commonly used models of breast cancer. This functional profile was integrated with accompanying molecular profiling datasets, such as gene mutation status, transcriptomic data, and hormone receptor status.

The investigators found that functional screening identified validated targets such as ERBB2 and PIK3CA. Other potential therapeutic targets were indentified, including those for PTEN-mutated and ER-positive breast cancers. The TTK protein kinase gene was identified as a candidate therapeutic target for PTEN-deficient tumors. TTK inhibition exacerbates an underlying aneuploidy or genomic instability possessed by the PTEN-null cells. The combination of PTEN mutation, and TTK inhibition influences cellular fitness more than either defect alone. In ER-positive breast tumor cell lines, ADCK2 silencing abolishes estrogen signaling. ADCK2 inhibitors are not currently available, but could be possible candidate targets for future drug development.

"Analysis of these profiles identifies a series of novel genetic dependencies, including that of PTEN-null breast tumor cells upon mitotic checkpoint kinases, and provides a framework upon which additional dependencies and candidate therapeutic targets may be identified," the authors write.

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