p-Glycoprotein ABCB5 and YB-1 expression plays a role in increased heterogeneity of breast cancer cells: correlations with cell fusion and doxorubicin resistance

Abstract

BackgroundCancer cells recurrently develop into acquired resistance to the administered drugs. The iatrogenic mechanisms of induced chemotherapy-resistance remain elusive and the degree of drug resistance did not exclusively correlate with reductions of drug accumulation, suggesting that drug resistance may involve additional mechanisms. Our aim is to define the potential targets, that makes drug-sensitive MCF-7 breast cancer cells turn to drug-resistant, for the anti-cancer drug development against drug resistant breast cancer cells.MethodsDoxorubicin resistant human breast MCF-7 clones were generated. The doxorubicin-induced cell fusion events were examined. Heterokaryons were identified and sorted by FACS. In the development of doxorubicin resistance, cell-fusion associated genes, from the previous results of microarray, were verified using dot blot array and quantitative RT-PCR. The doxorubicin-induced expression patterns of pro-survival and pro-apoptotic genes were validated.ResultsYB-1 and ABCB5 were up regulated in the doxorubicin treated MCF-7 cells that resulted in certain degree of genomic instability that accompanied by the drug resistance phenotype. Cell fusion increased diversity within the cell population and doxorubicin resistant MCF-7 cells emerged probably through clonal selection. Most of the drug resistant hybrid cells were anchorage independent. But some of the anchorage dependent MCF-7 cells exhibited several unique morphological appearances suggesting minor population of the fused cells maybe de-differentiated and have progenitor cell like characteristics.ConclusionOur work provides valuable insight into the drug induced cell fusion event and outcome, and suggests YB-1, GST, ABCB5 and ERK3 could be potential targets for the anti-cancer drug development against drug resistant breast cancer cells. Especially, the ERK-3 serine/threonine kinase is specifically up-regulated in the resistant cells and known to be susceptible to synthetic antagonists.

Metabolic restriction of cancer cells in vitro causes karyotype contraction—an indicator of cancer promotion?

“…NCI-H460 and COLO 320DM chromosome numbers are almost normalized by anoxia alone, possibly indicating a deeper dependence on oxygen metabolism. The apparent failure to reach peri-normal numbers in MCF7 may be due to the induction of cell fusions by the metabolic restrictors [35].…”

CHIP buffers heterogeneous Bcl-2 expression levels to prevent augmentation of anticancer drug-resistant cell population

“…3,4 Recent studies have indicated that anticancer drug-resistant cells are derived from emerging clones within primary tumors. 5,6 Anticancer drug resistance of cancer cells can occur via several mechanisms, including evasion of apoptosis, increased drug efflux and drug inactivation, 7 and corresponds closely to the prognosis of breast cancer patients. 5 Treatment failure in over 90% of metastatic cancer patients is believed to be caused by anticancer drug resistance.…”

“…5,6 Anticancer drug resistance of cancer cells can occur via several mechanisms, including evasion of apoptosis, increased drug efflux and drug inactivation, 7 and corresponds closely to the prognosis of breast cancer patients. 5 Treatment failure in over 90% of metastatic cancer patients is believed to be caused by anticancer drug resistance. 8 As remarked above, anticancer drug resistance is thought to occur in emerging clones caused by cancer heterogeneity.…”

Skin detoxification cycles

“…Recently Yang et al studied the role of cellular fusion and chemo-resistance with the MCF-7 breast cancer cell line, finding that the p-glycoprotein is involved in the heterogeneity of these cells and their chemo-resistance to doxorubicin. [8] Thus the ABCB5 pump must give the benign and malignant melanocyte an advantage in fissioning with fibroblasts, keratinocytes and other cellular lineages. [2,8] The malignant melanocyte camouflages itself and subjugates neighboring normal cells, and in this way establishes an adequate microenvironment that gradually extends itself.…”

“…[8] Thus the ABCB5 pump must give the benign and malignant melanocyte an advantage in fissioning with fibroblasts, keratinocytes and other cellular lineages. [2,8] The malignant melanocyte camouflages itself and subjugates neighboring normal cells, and in this way establishes an adequate microenvironment that gradually extends itself. The p-glycoprotein ABCB5 is crucial in this process of camouflage and subjugation of neighboring cells, and therefore for the malignancy of cancer.…”