Topotecan‐induced ABCG2 expression in MCF‐7 cells is associated with decreased CD24 and EpCAM expression and a loss of tumorigenicity

Abstract

Human breast cancer shows a considerable heterogeneity regarding the expression of CD24, CD44, EpCAM, and HER2. These markers are involved in cell adhesion, migration, and proliferation, and thus affect metastasis and, in turn, patient's outcome. The ATP-driven efflux pump (ABC transporter) breast cancer resistance protein (BCRP, ABCG2) is known to confer resistance to a wide variety of structurally unrelated cytostatics and defines subpopulations with enhanced tumor-initiating capacity. The expression of ABCG2 can be induced by treatment with different cytostatic drugs. Concurrent effects of such treatments on the expression of the aforementioned marker proteins and cellular properties related to cancer-initiating cells have not been examined thoroughly. Here, we investigated the effect of the ABCG2 substrate topotecan on the MCF-7 breast cancer cell line and analyzed CD24, CD44, EpCAM, and HER2 expression by flow cytometry. Moreover, we examined the impact of topotecan treatment on the sphere-forming ability in vitro and the tumorigenicity in immunodeficient NMRInu/nu and NSG mice. We found an elevated ABCG2 expression in MCF-7 cells in the presence of 500 nM topotecan. Compared with untreated MCF-7 cells, the application of topotecan induced a subpopulation with decreased CD24/EpCAM expression, whereas CD44 expression remained largely unchanged. Topotecan-treated cells showed an impaired mammosphere formation capacity in vitro and reduced tumorigenicity in immunodeficient mice. The data indicate that ABCG2 induction is not necessarily linked to increased tumorigenicity and suggest a major role of CD24 and EpCAM for the preservation of self-renewal capacity in MCF-7 cells and tumor outgrowth in vivo. V C 2015 International Society for Advancement of Cytometry

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

“…On average, the CA-4 resistant HT-29 colon carcinoma and the multi-drug resistant MCF-7 Topo mamma carcinoma cells were least sensitive to 4a – i [29,30]. In contrast, 4a – i were most active against 518A2 melanoma, HCT-116 colon carcinoma, and endothelial hybrid cells Ea.Hy926.…”

mdm2 gene amplification is associated with luminal breast cancer progression in humanized PDX mice and a worse outcome of estrogen receptor positive disease

“…However, it is becoming more and more obvious that this phenotype alone may not appropriately envisage the initiation of tumor growth, progression and metastasis 27‐30 . Moreover, a number of functional studies unambiguously indicate that an elevated CD44/CD24 expression ratio taken alone is neither sufficiently representative for the colony forming capacity in vitro nor for the initiating of tumor growth in vivo 15,31,29,32 . Thus, a multifactorial phenotype and genotype that includes a variety of markers known to be not only involved in but also to be essential for tumor stemness can be considered more robust to predict onset of tumor growth or tumor relapse after therapy.…”

“…[27][28][29][30] Moreover, a number of functional studies unambiguously indicate that an elevated CD44/CD24 expression ratio taken alone is neither sufficiently representative for the colony forming capacity in vitro nor for the initiating of tumor growth in vivo. 15,31,29,32 Thus, a multifactorial phenotype and genotype that includes a variety of markers known to be not only involved in but also to be essential for tumor stemness can be considered more robust to predict onset of tumor growth or tumor relapse after therapy. c-Met, CD44 and CD47 have been previously described to be part of an enhanced capacity to initiate metastasis of Luminal BC in a preclinical mouse model.…”

Revisiting the anticancer properties of phosphane(9-ribosylpurine-6-thiolato)gold(I) complexes and their 9H-purine precursors

“…In addition, most tested complexes were of similar cytotoxicity against KB-V1 cervix carcinoma cells in the absence and presence of the Pgp-substrate verapamil, clinically used to re-sensitize resistant tumors [ 31 ]. This suggests that these complexes are not substrates of ABC-transporter-type efflux pumps [ 32 , 33 ].…”