Postdoctoral associate, Indian institute of science, Bangalore
How does the phenotypic diversity among the tumor heterogeneity contribute in drug resistance
Drug treatment induces phenotypic switch and stemness in acquiring resistance
The conventional anti-cancer therapy is becoming a challenge to abolish tumor due to the development of drug resistance. Tumor cells acquire resistance due to intra-tumor heterogeneity imposed by epithelial to mesenchymal transition. The drugs which target epithelial cells may fail to target mesenchymal and the intermediate phenotypes due to which the cancer cells acquire drug resistance. This concept provoked us to understand the phenotypic diversity among the tumor heterogeneity which might lead to drug resistance. Treatment of breast cancer cell lines MCF7 and MDA MB 231 with Doxorubicin showed a loss of epithelial markers and gain of mesenchymal markers, and vice versa in MDA MB 231 cells, thereby shifting to an intermediate phenotype. Furthermore, Doxorubicin treatment of MDA MB 231-nanog stable cells led to an increase in nanog positive cells. Thus, our current data suggests that the anti-cancer therapy induces cancer cells to undergo a phenotypic switch and increases the stemness property which might be responsible to gain resistance. Identification of the critical regulators of the phenotypic switch by phosphoproteomics analysis may help us investigate the possible mechanisms underlying the anti-cancer drug resistance. Previous reports also suggest that conventional therapies fail to eliminate cancer stem cells thereby letting the tumor relapse. Our present study might contribute in understanding the possible mechanism of anti-cancer drug resistance and hence might help improve the clinical therapy.
Abstract: It is not well established whether miR-93 is involved in drug resistance and epithelial-mesenchymal transition (EMT) in breast cancer, and its underlying mechanism remains uncertain. In the present study, the expression differences of miR-93 between paired breast cancer tissues confirmed it is involved in the progression of breast cancer. Such a difference was also observed in doxorubicin-resistant and -sensitive cells. Overexpressed miR-93 in sensitive cells revealed increases in cellular proliferation and the expression levels of drug-resistant-related genes, and a decrease in sensitivity to doxorubicin. This demonstrated the relationship between miR-93 and breast cancer drug resistance. Simultaneously, EMT was confirmed in miR-93 overexpressing sensitive cells. This indicated the triadic relationship among miR-93, EMT and drug resistance in breast cancer. We applied the Dual-luciferase Reporter assay to expose the direct interaction between miR-93 and PTEN, which suggested that miR-93 contributes to inducing EMT and drug resistance of breast cancer cells by targeting PTEN.
Pub.: 03 Aug '17, Pinned: 12 Oct '17
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