**1. Introduction**

342 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

Zhang, Z., H. Yamashita, T. Toyama, H. Sugiura, Y. Ando, K. Mita, M. Hamaguchi, Y. Hara,

Zhao, W., Q. Zhang, X. Kang, S. Jin and C. Lou (2009). "AIB1 is required for the acquisition

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migration and invasion induced by HGF." Cancer Lett 280 (1): 78-85.

invasive carcinoma of the breast\*." Breast Cancer Res Treat 94 (1): 11-6. Zhang, Z., H. Yamashita, T. Toyama, H. Sugiura, Y. Omoto, Y. Ando, K. Mita, M.

better survival in breast cancer." Clin Cancer Res 10 (20): 6962-8.

cells." Biochem Biophys Res Commun 380 (3): 699-704.

S. Kobayashi and H. Iwase (2005). "Quantitation of HDAC1 mRNA expression in

Hamaguchi, S. Hayashi and H. Iwase (2004). "HDAC6 expression is correlated with

of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer

SMYD3 by RNA interference down-regulates c-Met expression and inhibits cells

Breast cancer is one of the most common and serious malignancies worldwide. Despite intensive cancer control efforts, it remains the second-leading cause of cancer death among women (Harris et al., 2000). While the overall response rate can be high, the duration of response is relatively short, and most patients with initially responsive tumors will experience a drug-resistance phenotype. Therefore, a lot of studies have centered on the field of drug resistance to improve cancer chemotherapy and management of cancers Gottesman, 2002).

The development of intrinsic or acquired resistance to a wide variety of anticancer drugs is a major obstacle to successful cancer chemotherapy. Some cancers show primary resistance or natural resistance in which they do not respond to standard chemotherapy drugs from the beginning. On the other hand, many types of sensitive tumors respond well to chemotherapy drugs in the beginning but show acquired resistance later (Choi, 2005). Multidrug resistance (MDR) can be defined as the intrinsic or acquired resistance of cancer cells to multiple classes of structurally and mechanistically unrelated antitumor drugs (Teodori et al., 2002). To date, the most widely studied cellular mechanisms of MDR are those associated with drug efflux involving members of the adenosine triphosohate-binding cassette (ABC) membrane transporter family (Mao et al., 2005).

Recently, several human ABC transporters with a potential role in drug resistance have been discovered. Among them, a novel known protein is ATP-binding cassette sub-family G member 2 (ABCG2). Human ABCG2 (also known as MXR, BCRP, and ABCP) was first cloned by Doyle et al. (Doyle et al., 1998) in the drug-resistant breast cancer cell line (MCF-7). ABCG2 is an efflux pump, which transports a variety of xenobiotics and endogenous compounds across cellular membranes. Tissue localization of ABCG2 in the mammary glands, intestine, kidney, liver, ovary, testis, placenta, endothelium and in hematopoietic stem cells indicates that ABCG2 plays an important role in absorption, distribution, and elimination of its substrates (Krishnamurthy et al., 2004; Mao & Unadkat, 2005). The expression of ABCG2 protein and/or mRNA has been detected in numerous types of human cancers (Diestra et al., 2002; Ross et al., 2000), and a large spectrum of anticancer drugs are effluxed by ABCG2

MCF-7 Breast Cancer Cell Line, a Model for the Study of the Association

1998; Walther et al., 1994; Walther et al., 1995).

protein levels (B) in MCF-7 cells.

Fig. 1. The effects of proinflammatory cytokines on ABCG2 mRNA expression (A) and

1β or TNF-α (Fig. 1).

Between Inflammation and ABCG2-Mediated Multi Drug Resistance 345

Piquette-Miller et al., 1998; Stein et al., 1997; Sukhai et al., 2001; Theron et al., 2003; Vos et al.,

The influence of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) on ABCG2 expression and function in human MCF-7 breast cancer cell line were studied using real-time PCR and flow cytometry, respectively. The results showed that, the levels of ABCG2 mRNA, protein expression and function in MCF-7 cells increased significantly after treatment with either IL-

(Doyle et al., 2003). It has also been shown that ABCG2 expression may be associated with poor response to chemotherapy (van den Heuvel-Eibrink et al., 2002, Steinbach, 2002 #216) . Alteration in ABCG2 expression and function can significantly affect the disposition of the transporter drug substrates, it is possible that its overexpression in cancer cells is responsible for decreasing in drug concentration within the cell and a reduced cancer-chemotherapy efficacy (Glavinas et al., 2004; Mao & Unadkat, 2005).

Inflammation is a state consisting of complex cytological and chemical reactions that occur in affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by physical, chemical or biological agents (Ho et al., 2006; Philip et al., 2004). Although inflammation is essential, it can be harmful to the host and therefore it is subject to multiple levels of biochemical, pharmacological, and molecular controls involving a diverse and potentially huge array of cell types and soluble mediators including cytokines (Haddad, 2002). In fact tumors are similar to healing or desmoplastic tissue in many ways and the micro-environment of the tumor highly resembles an inflammation site (Caruso et al., 2004). Breast cancer is a prototype of these kinds of cancer. Indeed, proinflammatory cytokines have been found to be present within the microenvironment of breast carcinomas and secreted by infiltrating host leukocytes, malignant and/or stromal cells of the breast cancer (Basolo et al., 1996; Jin et al., 1997; Lithgow et al., 2005; Miles et al., 1994).

In recent years, it has been demonstrated that the expression and function of the MDR transporters is altered in numerous tissues during an inflammatory response. The current review focuses on the elucidation of the effects of inflammation on the ABCG2 expression and function, using MCF-7 human breast carcinoma cell line.
