Quantifying Risk Pathway Crosstalk Mediated by miRNA to Screen Precision drugs for Breast Cancer Patients.

ABSTRACT

Breast cancer has become the most common cancer that leads to women's death. Breast cancer is a complex, highly heterogeneous disease classified into various subtypes based on histological features, which determines the therapeutic options. System identification of effective drugs for each subtype remains challenging. In this work, we present a computational network biology approach to screen precision drugs for different breast cancer subtypes by considering the impact intensity of candidate drugs on the pathway crosstalk mediated by miRNAs. Firstly, we constructed and analyzed the subtype-specific risk pathway crosstalk networks mediated by miRNAs. Then, we evaluated 36 Food and Drug Administration (FDA)-approved anticancer drugs by quantifying their effects on these subtype-specific pathway crosstalk networks and combining with survival analysis. Finally, some first-line treatments of breast cancer, such as Paclitaxel and Vincristine, were optimized for each subtype. In particular, we performed precision screening of subtype-specific therapeutic drugs and also confirmed some novel drugs suitable for breast cancer treatment. For example, Sorafenib was applicable for the basal subtype treatment, Irinotecan was optimum for Her2 subtype treatment, Vemurafenib was suitable for the LumA subtype treatment, and Vorinostat could apply to LumB subtype treatment. In addition, the mechanism of these optimal therapeutic drugs in each subtype of breast cancer was further dissected. In summary, our study offers an effective way to screen precision drugs for various breast cancer subtype treatments. We also dissected the mechanism of optimal therapeutic drugs, which may provide novel insight into the precise treatment of cancer and promote researches on the mechanisms of action of drugs.