The epigenetic silencing of tumor suppressor genes (TSG) in cancer offers the possibility to recover their dormant function using artificial transcription factors (ATF). Here, we compared the use of a well-established zinc finger (ZF) based ATF to re-activate Mammary Serine Protease Inhibitor (Maspin), a highly methylated TSG in metastatic breast cancer (1), with a new approach using a RNA-guided inactive endonuclease, dCas9, from the CRISPR (clustered regularly interspaced short palindromic repeats) bacterial system. Both ATFs were engineered with a transactivator domain and targeted to the same region of the proximal promoter of the target gene. We performed reporter assays and gene expression analysis by qPCR of the mRNA levels of Maspin to compare the competency of each system in two different cell lines (HEK293T and MCF7) transiently transfected using Lipofectamine 2000 (Invitrogen). We found an upregulation of up to 15-fold in the luciferase assays with CRISPR-ATF and 20-fold with ZF-ATF (p<0,001). However, the endogenous mRNA upregulation of Maspin showed a significant increase (p<0,001) of up to 35-fold using CRISPR-ATF, meanwhile ZF-ATF reached up to 28-fold compared to control (empty vector). We showed that a mix of four RNA-guides with dCas9-VP64 was able to re-activate endogenous Maspin more effectively than a single ZF-VP64. Compared with ZF technology, the more selective target recognition method of the CRISPR-ATFs (RNA-DNA pairing compared to protein-DNA interaction) allowed us the use of multiple guides at low amounts each, decreasing potential off-target effects. Thus, the technical advantages of the CRISPR based ATFs make them a promising new technique for developing a novel epigenetic therapy for breast cancer.