Gsk-3β

Despite continuous advances in the knowledge of breast cancer pathophysiology, this type of neoplasia remains a leading cause of cancer-related death in women, with more than 450 000 deaths every year worldwide. 1 surgery, coupled with radiation and/or che-motherapy, remains the main approach for breast cancer treatment. However, another common therapeutic option is based on the use of the estrogen receptor (eR) antagonist, tamoxifen. 2 indeed, approximately 60–70% of early-stage breast cancers overexpress the eR, making their growth dependent on estro-gens. Tamoxifen blocks estrogen signaling by competitively binding the eR, thus antagonizing its proliferative and pro-survival effects. Breast cancers can be inherently drug-resistant or develop resistance after exposure to chemotherapeutic drugs, such as the anthracyline, doxorubicin. 1 Resistance can also develop in patients receiving tamoxi-fen. 2 Therefore, it is very important to understand how breast cancers become drug-and hormone-resistant, and whether or not their drug-resistance can be reversed. There also is a need for novel targeted therapies for breast cancer patients who develop resistance to traditional therapies. GsK-3β is a serine/threonine kinase involved in several signal transduction cascades , including the Pi3K/Akt/mTOR, wnt/β-catenin, and MeK/eRK pathways. 3 in particular, Akt and other kinases phosphorylate GsK-3β at ser9. This phosphorylative event inactivates GsK-3β3. GsK-3β regulates cell cycle progression , differentiation, survival, embryogenesis, migration, and metabolism. However, aberrant GsK-3β activity has been linked with an increasing number of pathologies, including cancer, heart disease, immune system disorders , diabetes, atherosclerosis, and different neurological diseases. 3 Although its role in cancer remains controversial , GsK-3β has also been implicated in breast cancer development and drug resistance. Using eR-positive MCF-7 breast cancer cells, sokolosky and coworkers have performed a detailed analysis of the roles played by GsK-3β in causing resistance to doxorubicin or tamoxifen. 6 They found that MCF-7 cells overexpressing a kinase-dead (KD) form of GsK-3β were more resistant to doxo-rubicin and tamoxifen compared with MCF-7 cells overexpressing either wild-type (wT) or constitutively active (CA) GsK-3β. ectopic expression of GsK-3β(KD) also resulted in increased clonogenic activity of MCF-7 cells in comparison with either GsK-3β(wT) or GsK-3β(CA) overexpression. Moreover, treatment of parental MCF-7 and MCF-7/GsK-3β(wT) cells with doxorubi-cin abrogated the phosphorylation of GsK-3β at ser9. in contrast, ser9 p-GsK-3β was still detectable in MCF-7/GsK-3β(KD) and MCF-7/ GsK-3β(CA) cells. This indicated that one of the effects of doxorubicin on MCF-7 cells was suppression of ser9 p-GsK-3β, which could then result in increased GsK-3β activity. Downregulation of …