Cancer Cell Article Protein Kinase C a Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells

be eliminated while leaving behind CSC-enriched cells that pro-more resistant CSCs that can subsequently generate clinica within tumors. The identification of key regulatory mechanisms that distinguish CSCs from non-CSCs is therefore critical for CSC-targeted therapy. We find that the PKCa signaling network is activated specifically in CSCs, rendering them pref-erentially susceptible to specific pharmacologic agents. In addition, we uncovered FRA1 to be a key transcription factor downstream of PKCa that drives CSC function. The inhibition of either PKCa or FRA1 can abolish tumor initiation, high-lighting the potential therapeutic value of targeting these proteins in epithelial cancers such as breast cancer.Cancer stem cells (CSCs), which are defined by their tumor-initi-ating properties, have been identified within breast, colon, head and neck, lung, and prostate carcinomas (Ailles and Weissman, 2007). These cells appear to be responsible for driving tumor growth, recurrence, and metastasis (Al-Hajj et al., 2003; Dalerba et al., 2007). In experimental models of cancer development, treatment of bulk cancer cell populations within tumors or cancer cell lines propagated in culture with chemotherapy or radio-therapy has been shown to select for the outgrowth of therapy-resistant subpopulations of cancer cells that are more tumorigenic, invasive, and stem like (Creighton et al., 2009; Gupta et al., 2009). Hence, cancer therapies may be rendered ceed to regenerate tumors. These tumors are often more malig-nant than was observed prior to treatment, underscoring the need for a detailed understanding of the molecular differences between CSCs and non-CSCs to discover and exploit cell-state-specific features that may render CSCs susceptible to selective therapeutic intervention. Numerous studies have used existing cancer cell lines to iden-tify compounds that target cells bearing specific gene mutations or exhibiting a more malignant phenotype; these studies did not, however, address the specific effects of certain treatments on CSCs because the representation of CSCs within these cell lines was poorly defined. In the case of breast cancer, severa