Strategies for the discovery and development of therapies for metastatic breast cancer

Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 06/2012; 11(6):479-97. DOI: 10.1038/nrd2372
Source: PubMed

ABSTRACT Nearly all deaths caused by solid cancers occur as a result of metastasis--the formation of secondary tumours in distant organs such as the lungs, liver, brain and bone. A major obstruction to the development of drugs with anti-metastatic efficacy is our fragmented understanding of how tumours 'evolve' and metastasize, at both the biological and genetic levels. Furthermore, although there is significant overlap in the metastatic process among different types of cancer, there are also marked differences in the propensity to metastasize, the extent of metastasis, the sites to which the tumour metastasizes, the kinetics of the process and the mechanisms involved. Here, we consider the case of breast cancer, which has some marked distinguishing features compared with other types of cancer. Considerable progress has been made in the development of preclinical models and in the identification of relevant signalling pathways and genetic regulators of metastatic breast cancer, and we discuss how these might facilitate the development of novel targeted anti-metastatic drugs.

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    • "Both intracellular and secreted galectin-3 were detectable in PC-3 cells and culture medium (Figure 4I-A). MDA-MB-231 also has high metastatic potential to bone in an intra-cardiac injection model and causes osteolytic lesions [4], and the cells both expressed endogenous galectin-3 and secreted it (Figure 4I-A). LNCaP and BT-549 cells were devoid of galectin-3 (Figure 4I-A) and were transfected with p3xflag-myc-cmv-25 plasmid containing the preprotrypsin leader sequence as a secretory signal peptide for secretion of expressed protein into the culture medium. "
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    ABSTRACT: Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2, SP7, ALPL, COL1A1, IBSP, and BGLAP, of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target.
    Neoplasia (New York, N.Y.) 11/2014; 16(11). DOI:10.1016/j.neo.2014.09.005 · 5.40 Impact Factor
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    • "Although patients with breast cancer metastases generally have high mortality rates and a very poor prognosis, over the last decades the progresses in medical management have improved clinical outcomes, so women are living longer with progressive disease (Arslan et al., 2011; Lyman et al., 2012). When breast cancer patients develop distant metastases, the choice of systemic treatment with chemotherapy, hormonal therapy, antiangiogenesis therapy, or human epidermal growth factor receptor 2 (HER2)-targeted therapy is based on assessment of specific cancer receptor types in the primary tumor using routine immunohistochemistry (IHC) and/ or molecular analysis (Cortazar et al., 2012; Eckhardt et al., 2012). The most common receptors that play a key role in metastatic breast cancer are estrogen receptor "
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    ABSTRACT: Background: Previous reports have shown that human epidermal receptor (HER)-3 overexpression may be associated with poor prognosis in patients with breast cancer, but results have been conflicting. In this study, we sought to investigate the prognostic significance of HER-3 immunohistochemical expression in patients with metastatic breast cancer. Methods: We retrospectively analyzed HER-3 immunohistochemical expression profiles in 45 paraffin-embedded specimens from patients who had been treated between 1996 and 2006 in the Department of Oncology of the Uludag University School of Medicine, Bursa, Turkey. Membranous or cytoplasmic dominant expression patterns of HER-3 were analyzed using the Rajkumar score and a cytoplasmic 4-point scoring system, respectively. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. Results: The median PFS in the study participants was 9 months (interquartile range: 4.5-13 months), whereas the median OS was 20 months (interquartile range: 7.5-28 months). Categorization of the patient population according to HER-3 positive immunohistochemical expression did not reveal any statistically significant difference in terms of both PFS (p=0.70) and OS (p=0.81). The results of multivariable Cox regression analysis indicated that tumor size was the only independent predictor of PFS, whereas estrogen and progesterone receptor status was independently associated with OS. Conclusions: HER-3 immunohistochemical expression did not correlate with outcomes in Turkish patients with metastatic breast cancer. Although our results suggest that HER-3 expression in cancer specimens is not of prognostic significance, further prospective studies are warranted to confirm these results.
    Asian Pacific journal of cancer prevention: APJCP 07/2013; 14(7):4115-9. DOI:10.7314/APJCP.2013.14.7.4115 · 2.51 Impact Factor
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    • "However, site specific organotropism is a complex process involving not only TGF-β but the tumor cell genotype and tumor–stroma interactions at the primary site and target organ (Lu and Kang, 2007; Eckhardt et al., 2012; Ganapathy et al., 2012). The various facets of each of these metastatic sites in conjunction with TGF-β are addressed elsewhere (Nishizuka et al., 2002; Lu and Kang, 2007; Drabsch and ten Dijke, 2011; Eckhardt et al., 2012). "
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    ABSTRACT: The components that comprise the extracellular matrix (ECM) are integral to normal tissue homeostasis as well as the development and progression of breast tumors. The secretion, construction, and remodeling of the ECM are each regulated by a complex interplay between tumor cells, fibroblasts and macrophages. Transforming growth factor-β (TGF-β) is an essential molecule in regulating the cellular production of ECM molecules and the adhesive interactions of cells with the ECM. Additionally, hypoxic cell signals, initiated by oxygen deprivation, additional metabolic factors or receptor activation, are associated with ECM formation and the progression of breast cancer. Both TGF-β and hypoxic cell signals are implicated in the functional and morphological changes of cancer-associated-fibroblasts and tumor-associated-macrophages. Moreover, the enhanced recruitment of tumor and stromal cells in response to hypoxia-induced chemokines leads to increased ECM deposition and remodeling, increased blood vessel formation, and enhanced tumor migration. Thus, elucidation of the collaborative networks between tumor and stromal cells in response to the combined signals of TGF-β and hypoxia may yield insight into treatment parameters that target both tumor and stromal cells.
    Matrix biology: journal of the International Society for Matrix Biology 12/2012; 32(2). DOI:10.1016/j.matbio.2012.11.016 · 3.65 Impact Factor
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