Combining chemo-, hormonal and targeted therapies to treat breast cancer

Breast cancer ranks as the second most common cause of cancer death among women in the United States. Anticancer agents are an important component of breast cancer therapy. Drugs frequently used to treat breast cancer include methotrexate, 5-fluorouracil (5-FU), cyclophosphamide, anthracyclines, taxanes, trastuzumab, tamoxifen and aromatase inhibitors. These agents inhibit breast cancer progression by a variety of different mechanisms. Mutations may occur in cancer cells, which result in the elevated expression or constitutive activation of various growth factor receptors. The Raf/MEK/ERK and PI3K/Akt pathways are often activated by mutations in these growth factor receptors. These pathways are regulated by upstream Ras, which is mutated in 20-30% of human cancers. Downstream B-Raf and PI3K are also activated by mutation. Many of the events elicited by the Raf/MEK/ERK and PI3K/Akt pathways have direct effects on survival and the proliferative pathways. Aberrant regulation of the Raf/MEK/ERK and PI3K/Akt pathways can contribute to uncontrolled cell growth and lead to malignant transformation. Effective targeting of these pathways may result in the suppression of cell growth and the death of malignant cells. This review focuses on the targeting of the Raf/MEK/ERK and PI3K/Akt pathways with small molecule inhibitors, as well as on the effects of conventional chemo- and hormonal therapies in the treatment of breast cancer.