FZD7 in Triple Negative Breast Cancer Cells

Breast cancer is the most prevalent cancer in women. Although the survival rate of breast cancer has improved steadily in the past two decades, over 40,000 women die from breast cancer related complications each year. The heterogeneity of breast cancer makes the treatment of different subtypes difficult (Gonzalez-Angulo et al., 2007; Perez et al., 2010). Triple negative breast cancer (TNBC) is one of the subtypes. It is negative for both estrogen and progesterone hormone receptors and lack the overexpression of human epidermal growth factor receptor 2 (HER2). TNBC constitutes approximately 15% of all breast cancers. However, its death rate is disproportionately higher than any other subtype of breast cancer, especially among young Black, Asian and Hispanic patients (Anders and Carey, 2009; Kassam et al., 2009; Rahman et al., 2009). Although, HER2 antibody, Herceptin, estrogen receptor antagonist, and aromatase inhibitor have brought hope to breast cancer patients, the treatment of TNBC remains to be a great challenge (Amir et al., 2010; Gluz et al., 2009; Silver et al., 2010). Thus it is imperative to investigate effective therapeutic targets for TNBC patients. FZD7, a Wnt pathway receptor, is one of the most abundant Frizzled family proteins expressed in TNBC and its cell lines. Wnt canonical signaling regulates cell fate decision throughout embryonic development and is related to human disease (Clevers, 2006; MacDonald et al., 2009; Reya and Clevers, 2005). Activation of Wnt canonical pathway is transduced through Frizzled (FZD) family receptors and LRP5/LRP6 coreceptor to the βcatenin signaling cascade (Bhanot et al., 1996; Pinson et al., 2000). In the presence of canonical Wnt signal, FZD binds to Dishevelled (DVL) and LRP5/6 to AXIN-FRAT to form a complex. β-catenin is protected from phosphorylation (Tolwinski et al., 2003) and the stabilized βcatenin translocates from the cytoplasm to the nucleus to activate the transcription of Wnt responsive genes by binding with T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors. Activation of these tissue-specific Wnt target genes is involved in the development of human tumors, including breast, colon, and other cancers (Jones and Kemp, 2008; Lee et al., 1995; Ojalvo et al., 2010). To investigate the therapeutic targets for TNBC, microarray has been performed to identify the genes that may be involved in the tumorigenesis of TNBC. FZD7 is differentially expressed in TNBC which raises the possibility that aberrant Wnt signaling might be critical for TNBC development. In this chapter we will address the role that FZD7 plays in cell proliferation of TNBC and its mechanism.