Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy.

Elucidating the response of breast cancer cells to chemotherapeutic and hormonal based drugs is clearly important as these are frequently used therapeutic approaches. A signaling pathway often involved in chemo-and hormonal-resistance is the Ras/PI3K/PTEN/Akt/mTOR cascade. In the studies presented in this report, we have examined the effects of constitutive activation of Akt on the sensitivity of MCF7 breast cancer cells to chemotherapeutic-and hormonal-based drugs as well as mTOR inhibitors. MCF-7 cells which expressed a constitutively-activated Akt-1 gene [.Akt-1(CA)] were more resistant to doxorubicin, etoposide and 4-OH-tamoxifen (4HT) than cells lacking.Akt-1(CA). Cells which expressed Delta Akt-1(CA) were hypersensitive to the mTOR inhibitor rapamycin. Furthermore, rapamycin lowered the IC(50)s for doxorubicin, etoposide and 4HT in the cells which expressed Delta Akt-1(CA), demonstrating a potential improved method for treating certain breast cancers which have deregulated PI3K/PTEN/Akt/mTOR signaling. Understanding how breast cancers respond to chemo-and hormonal-based therapies and the mechanisms by which they can become drug resistant may enhance our ability to treat breast cancer. These results also document the potential importance of knowledge of the mutations present in certain cancers which may permit more effective therapies

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