**3. Breast cancer therapy**

To date, adjuvant and neo-adjuvant therapies are commonly used in cancer metastasis therapy (McGrogan et al, 2008). Currently, there are three main groups of medications used for adjuvant breast cancer treatment: (1) hormone blocking therapy; (2) chemotherapy; and (3) monoclonal antibody therapy (McGrogan et al, 2008). The cell surfaces of some breast cancers are estrogen receptors positive (ER+) and/or progesterone receptors positive (PR+) and the cells require estrogen to continue growing. These cancers can be treated with drugs that block either the hormone receptors, such as tamoxifen or the production of estrogen, such as anastrozole (Arimidex) or letrozole (Femara). The drugs that inhibit estrogen production are only suitable for post-menopausal patients (Gonzalez-Angulo et al, 2007). Combination chemotherapy is predominately used for patients at stages 2-4, being particularly beneficial in ER-breast cancer. One of the most common treatments is cyclophosphamide plus doxorubicin (Adriamycin) which destroys rapidly growing or replicating cancer cells by causing DNA damage; however, these drugs also damage normal cells causing serious adverse effects. Damage to heart muscle is the most dangerous complication associated with doxorubicin. Taxane drugs such as paclitaxel, a microtubulestabilizing agent that interferes with spindle microtubule dynamics causing cell-cycle arrest and apoptosis through interaction with β-tubulin (Bergstralh & Ting, 2006), is also used in the breast cancer metastasis therapy. However, resistance to paclitaxel is common and there

In the United States, about 178,480 new cases of invasive breast cancer were diagnosed in 2007 and approximately 40,460 women died (Jemal et al, 2007). In 2010, about 207,090 new breast cancer cases were diagnosed and 39,840 died (Jemal et al, 2010). The breast cancer incidence rate has been decreasing in the USA since 1999 and the majority of 40,000 women died each year were due to breast cancer metastasis (Giordano & Hortobagyi, 2003; Jemal et al, 2010). Cancer metastasis is a complex process that includes intercellular and intracellular signaling, activation, adhesion, migration and invasion (Im et al, 2004; Lee et al, 2006). Epithelial-to-mesenchymal transition (EMT) is also thought to be involved in cancer metastasis. EMT may promote cancer-cell progression and invasion into the surrounding microenvironment. Historically, epithelial and mesenchymal cells are distinct in their unique cellular appearance and the morphology of the multicellular structures they create (Shook & Keller, 2003). A typical morphology of epithelium is sheeted and thick with individual epithelial cells abutting each other in a uniform array. Cell-to-cell junctions and adhesions between neighboring epithelial cells hold cells tightly together and inhibit the movement of individual cells away from the epithelial monolayer. Mesenchymal cells, on the other hand, possess usually a more extended and elongated shape and do not exhibit either a regimented structure or tight intracellular adhesion. Mesenchymal cells are irregular in shape and not uniform in composition or density. Adhesions between mesenchymal cells are not as strong as those of their epithelial counterparts, allowing for increased migratory capacity. The transformation of an epithelial cell into a mesenchymal cell not only alters cellular morphology, architecture, adhesion capacity, and migration capacity but also enhances capability of the cell to metastasize (Shook & Keller, 2003). Conversely, the transformation of a mesenchymal cell into an epithelial cell (MET) may prevent cell invasion

To date, adjuvant and neo-adjuvant therapies are commonly used in cancer metastasis therapy (McGrogan et al, 2008). Currently, there are three main groups of medications used for adjuvant breast cancer treatment: (1) hormone blocking therapy; (2) chemotherapy; and (3) monoclonal antibody therapy (McGrogan et al, 2008). The cell surfaces of some breast cancers are estrogen receptors positive (ER+) and/or progesterone receptors positive (PR+) and the cells require estrogen to continue growing. These cancers can be treated with drugs that block either the hormone receptors, such as tamoxifen or the production of estrogen, such as anastrozole (Arimidex) or letrozole (Femara). The drugs that inhibit estrogen production are only suitable for post-menopausal patients (Gonzalez-Angulo et al, 2007). Combination chemotherapy is predominately used for patients at stages 2-4, being particularly beneficial in ER-breast cancer. One of the most common treatments is cyclophosphamide plus doxorubicin (Adriamycin) which destroys rapidly growing or replicating cancer cells by causing DNA damage; however, these drugs also damage normal cells causing serious adverse effects. Damage to heart muscle is the most dangerous complication associated with doxorubicin. Taxane drugs such as paclitaxel, a microtubulestabilizing agent that interferes with spindle microtubule dynamics causing cell-cycle arrest and apoptosis through interaction with β-tubulin (Bergstralh & Ting, 2006), is also used in the breast cancer metastasis therapy. However, resistance to paclitaxel is common and there

**2. Breast cancer metastasis** 

and suppress cell metastatic ability.

**3. Breast cancer therapy** 

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

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 resettlement and metastatic growth continues.
