Despite extensive efforts to understand why
chemoresistance occurs, there are few successful strategies in the clinic to
overcome it or predict the treatment response. This is partly because most
research in this area relies on expression data and correlative studies,
without delving into the mechanisms of drug resistance. Here we focus on
microRNAs—small non-coding RNAs that regulate gene expression—and employ
functional genomics to explain how they control cancer’s sensitivity to
chemotherapy. We performed genome-wide inhibition and overexpression of ~1500
microRNAs in four breast cancer models in
vitro, in the presence of two common molecularly distinct chemotherapeutic
drugs. Cell viability measurements revealed numerous cell-type- and
drug-type-specific synthetic lethal interactions where microRNA overexpression
or inhibition markedly increased the effects of the drugs. High-content
microscopy, in addition, enabled us to pinpoint the exact cellular
processes—such as apoptosis, proliferation, or EMT-like morphological
changes—that underlie these effects. To search for the underlying molecular
mechanisms and direct microRNA targets, we performed gene expression profiling
in cells expressing candidate microRNA mimics. Interestingly, our analysis
revealed that candidate microRNAs induce genome-wide changes in cellular
transcriptome and disregulation of numerous transcriptional regulators, cell
cycle and cytoskeleton components known to be crucial for breast carcinogenesis.
Rather then focusing on individual targets, we are currently developing methods
to construct microRNA-specific gene signatures that define our candidate
microRNAs and their striking effects on cancer cell viability. Taken together,
our study stands as the most comprehensive investigation of microRNA function
in cancer proliferation, survival, and chemosensitivity. As such, it will serve
as a discovery platform for the cancer research community at large as well as a
stepping-stone to the development of novel combination therapies.