ABCG2 is a potential marker of tumor-initiating cells in breast cancer

Abstract

The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2(+) cells in breast carcinomas is a marker of resistance to chemotherapy, and based on in vitro assays and the genetic profile, we show, for the first time, that ABCG2 protein can be used as an independent marker for TIC identification in breast cancer.

NMI inhibits cancer stem cell traits by downregulating hTERT in breast cancer

“…Recent evidence has shown that the ABC family of transporters is associated with CSCs. 25, 26, 27, 28 Thus, we also detected their expression when NMI was knocked down. The results showed that knockdown of NMI led to the increased expression of ABC transporter genes such as ABCG2 and ABCB1 (Supplementary Figure 1).…”

Wnt signaling in triple-negative breast cancer

“…110 These cells also have intrinsic mechanisms for chemoresistance, such as upregulation of drug transporters, including the breast cancer resistance protein (also known as ABCG 2 ). 111 By evading the standard chemotherapeutic treatments, it is thought that the CSCs are also responsible for the relapse experienced in many cancers, especially TNBCs. 112 Studies have also shown that these cells are a main contributor to metastasis, and are able to initiate solid tumor formation when xenotransplanted at low cell densities.…”

Multifunctional role of pancreatic stellate cells in pancreatic cancer

“…αSMA ×400 A B and TIMP2 to maintain the balance of extracellular matrix, which is usually disrupted after activation in pancreatitis and PDAC. Several in vitro and in vivo studies suggest that PSCs may have progenitor-like capabilities, possessing ATP-binding cassette G2 (ABCG2) and they transform into insulin-secreting cells upon exposure to the relevant culture medium (40,(43)(44)(45)(46).…”