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The cancer stem cell (CSC) hypothesis proposes that CSCs are the root of cancer and cause cancer metastasis and recurrence. In this study, we examined whether Ras signaling is associated with stemness of the CSCs population characterized by the stem cell antigen (Sca-1) phenotype in a 4T1 syngeneic mouse model of breast cancer. The Sca-1(pos) putative CSCs had high levels of activated Ras and phosphorylated MEK (p-MEK), compared with counterparts. The Ras farnesylation inhibitor (FTI-277) suppressed the maintenance and expansion of CSCs. Therefore, selective inhibition of Ras activation may be useful for stem-specific cancer therapy.

High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho-AKT. The introduction of dysadherin cDNA into BT-474, MCF-7 and T-47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA-MB-231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin-mediated pro-metastatic effects, including epithelial-mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation. (Cancer Sci 2012; 103: 1280-1289 B reast cancer is one of the most commonly detected malignancies in women worldwide.(1) The latest advances in cancer diagnosis and therapy have greatly improved survival of breast cancer patients. Metastasis is a destructive consequence of cancer progression and is the most common cause for treatment failure and death in breast cancer.(2) There is much to discover about the biological and molecular mechanisms that control the metastatic process.Dysadherin is a cancer cell membrane-associated glycoprotein that has been recognized as a prognostic indicator of metastasis and/or poor survival in many different cancer types. (3)(4)(5) The presence of dysadherin expression contributes causally to cancer metastasis in a number of ways, including downregulation of E-cadherin-mediated cell adhesion, upregulation of tumor-promoting chemokine production and enhancement of cancer stem-cell properties.(5-7) Based on these findings, dysadherin might represent a molecular target for the treatment of advanced cancer. The detailed molecular mechanisms that link dysadherin expression to downstream events that promote cancer metastasis have not been fully clarified. The elucidation of dysadherin signaling mechanisms in specific aspects of metastasis might lead to the development of effective therapies for treating advanced cancer.Nam et al. (5) show, in a breast cancer model system, that NF-jB transcriptional activity is enhanced by dysadherin expression. Specifically, NF-jB regulates the expression of genes involved in many cellular processes that play a key role in the development and progression of cancer.(8) NF-jB is intimately intertwined with cancer growth and metastasis; (9) the NF-jB transcription factor has been identified as a target of the AKT signaling pathway.(10) AKT is a serine/threonine kinase that plays a critical role in cell survival by negatively interacting with proteins that promote apopt...

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