Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

Breast cancer ranks as the second most common cause of cancer death among women in the United States. Only lung cancer, which results primarily from cigarette smoking, induces more cancer deaths in women in the USA. Approximately 1 in 7 women in the United States will be diagnozed with breast cancer during her lifetime (Jemal et al., 2004). Over 210,000 new cases of breast cancer are diagnozed in the United States each year (Centers for Disease Control and Prevention, 2006 Centers for Disease Control and Prevention, Cancer: symptoms of breast cancer, Centers for Disease Control and Prevention, Atlanta, GA (2006) http://www.cdc.gov/cancer/breast/basic_info/symptoms.htm.Centers for Disease Control and Prevention, 2006). Breast cancer is the cause of death of over 40,000 women in the United States each year. Many drugs have been demonstrated to extend survival of breast cancer patients. Anticancer agents frequently used to treat breast cancer include chemotherapeutic drugs such as methotrexate, 5-fluorouracil (5-FU), cyclophosphamide, anthracyclines, taxanes, monoclonal antibodies such as trastuzumab, hormonal based therapeutics such as tamoxifen and aromatase inhibitors. Mechanisms by which these agents inhibit breast cancer progression vary from drug to drug. While these drugs are the mainstay of chemo, immuno and hormonal therapy of breast cancer, a common problem with these treatments is the development of drug resistance. Breast cancer cells can become drug resistant by multiple mechanisms which include: increased expression of membrane transporters which transport the toxic drug out of the cell or modify/detoxify the drug, increased expression of signaling and anti-apoptotic pathways as well as other mechanisms which allow the cells to grow in the presence of the drug. This manuscript will discuss some of the mechanisms by which the altered expression of key signaling and apoptotic pathways may lead to breast cancer drug resistance and how targeting these pathways may result in the suppression of neoplastic growth.