**1.1 Breast cancer classification**

Breast cancer is one of the most common cancers among women worldwide and approximately one-third of women diagnosed will eventually develop metastases and die (Jemal et al, 2010). Breast cancer is heterogeneous at the molecular, histopathologic and clinical levels and is commonly classified into several categories according to multiple schemes, each based on different criteria. A typical description of breast cancer can be comprised of tumor grade, histologic type, tumor stage, and the expression of proteins and genes etc. (McSherry et al, 2007). Normal non-cancerous cells are differentiated and have specific cell shapes and functions; whereas, cancer cells lose differentiation (dedifferentiate), have less uniform nuclei, and exhibit uncontrolled cell division. Pathologists, therefore, determine breast cancer by grade according to the degree of differentiation of cells compared to normal breast cells: highly differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade). Cancers classified as high grade generally have a worse prognosis (McSherry et al, 2007). The majority of breast cancers are derived from the epithelium lining the ducts or lobules of the breast. They can be classified histologically according to characteristics seen upon light microscopy of biopsy specimens. Histologic classification is divided into: ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and invasive lobular carcinoma (McSherry et al, 2007). Breast cancer can further be classified using the TMN Classification of Malignant Tumors, TMN stage is based on tumor size, lymph node micrometastasis, and macrometastasis, where 'T' describes tumor size; 'N' indicates whether or not the tumor has spread to the lymph nodes; and 'M' indicates whether or not distant metastasis has occurred. Larger tumor size with lymph nodal spread and distal metastasis has a worse prognosis (Gonzalez-Angulo et al, 2007). Expression of certain proteins and genes can also be used to classify breast cancer (McGrogan et al, 2008; Stickeler et al, 2009). Whole-genome analysis using expression microarray and immunohistochemical analysis has revolutionized the understanding of breast carcinomas in recent years, and led to the discovery of five distinct subtypes of breast carcinomas (luminal A, luminal B, HER-2 overexpression, basallike, and normal-like), each with unique recognizable phenotypes and clinical outcomes (McGrogan et al, 2008; Stickeler et al, 2009). By using classification to characterize each cancer patient, it may help select the suitable treatment strategies to achieve an optimal outcome and increase therapeutic efficacy.

Fibrillar Human Serum Albumin Suppresses Breast Cancer Cell Growth and Metastasis 425

is a need to identify patients most likely to respond to treatment (McGrogan et al, 2008). Other treatments like methotrexate and fluorouracil are also used in chemotherapy. Approximately 15-20% of breast cancers have an amplification of the HER-2/neu gene or overexpression of its protein product. This receptor is a marker for poor prognosis that is associated with increased disease recurrence during the period of cancer therapy (Brown et al, 2008). Trastuzumab (Herceptin), a humanized monoclonal antibody that specifically binds to the extracellular domain of the HER-2 receptor, has improved the 5-year disease free survival of stage 1-3 HER-2+ breast cancers to about 87%. However, about 2% of patients suffer significant heart damage after Herceptin treatment (Brown et al, 2008). Trastuzumab has also been used in combination with doxorubicin and proven to be highly effective for metastatic breast cancer patients with HER-2 over-expressing tumors. However, this regimen causes severe cardiac toxicity in 27% of treated patients when the two substances are given concurrently (Stickeler et al, 2009). Lapatinib (Tykerb, GlaxoSmithKline) is an orally active small molecule that inhibits the tyrosine kinases of HER-2 and epidermal growth factor receptor type 1 (EGFR). In preclinical studies, lapatinib

Conventional radiotherapy is usually given after surgery to destroy remaining tumor cells that may have escaped surgery. Recently, radiotherapy has also been given at the time of surgery and found to reduce the risk of recurrence by 50-66% (Belletti et al, 2008). Despite such improvements in treatment modalities, there is still a high rate of failure among adjuvant interventions mainly due to tumor invasion and metastasis. Therefore, the search for new therapeutic targets and the development of new inhibitors of tumor cell

It is well known that cell activation, migration, proliferation, and differentiation require direct contact between cells and the extracellular matrix (ECM). Cell-to-cell and cell-tomatrix interactions are mediated by the integrin, selectin, cadherin and/or immunoglobulin families and several studies have focused on investigating cancer therapies based on the integrin superfamily. Integrin expression on cancer cells is frequently associated with cancer progression and metastasis; therefore, targeting small-molecule antagonists of the integrin superfamily provides an opportunity to suppress cancer development and metastasis (Mullamitha et al, 2007). β1 integrin, which frequently aberrantly expressed in human breast carcinomas, has been verified to play a central role in metastasis and contribute to growth factor receptor signaling. Inhibition of the 1 integrin signaling pathway has been shown to abolish the formation of metastasis in breast and gastric cancer models. Additionally, the 1 integrin signaling pathway also plays a significant role in mediating resistance to cytotoxic chemotherapies by enhancing cell survival in hematologic malignancies, lung, and breast cancers (Lu et al, 2008). Recent studies have shown that α1β1, α2β1, and α3β1 integrins regulate hepatocarcinoma cell invasion, angiogenesis of human squamous cell carcinoma, and increase migration and invasion of malignant glioma, melanoma and mammary adenocarcinoma cells, respectively. Expression of α5β1 integrin in colon cancer cells decreases HER-2-mediated proliferation (Kuwada et al, 2005). Loss of the α7β1 integrin in melanoma increases highly tumorigenic and metastatic phenotypes (Ziober et al, 1999). Several preclinical and clinical trials have shown that some integrin targeting antibodies can effectively block tumor growth and metastasis. These antibodies include MEDI-522 (vitaxin)

**4. Surface membrane integrins as potential drug-discovery targets** 

showed no cross-resistance with trastuzumab (Jahanzeb, 2008).

resettlement and metastatic growth continues.
