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Background  Over-expression of cyclooxygenase (COX)-2 promotes breast cancer progression by multiple mechanisms, including induction of stem-like cells (SLC). Combined gene expression and microRNA microarray analyses of empty vector vs  COX-2-  transfected COX-2 low MCF7 breast cancer cell line identified two COX-2-upregulated microRNAs, miR-526b and miR-655, both found to be oncogenic and SLC-promoting. Cytoplasmic Polyadenylation Element-Binding Protein 2 (CPEB2) was the single common target of both microRNAs, the functions of which remain controversial. CPEB2 has multiple isoforms (A-F), and paradoxically, a high B/A ratio was reported to impart anoikis-resistance and metastatic phenotype in triple- negative breast cancer cells. We tested whether CPEB2 is a tumor suppressor in mammary epithelial cells.    Methods  We knocked-out  CPEB2  in the non-tumorigenic mammary epithelial cell line MCF10A by CRISPR/Cas9-double nickase approach, and knocked-down  CPEB2  with siRNAs in the poorly malignant MCF7 cell line, both lines being high  CPEB2 -expressing. The resultant phenotypes for oncogenity were tested in vitro for both lines and in vivo for  CPEB2KO  cells. Finally , CPEB2  expression was compared between human breast cancer and non-tumor breast tissues.    Results   CPEB2  (isoform A) expression was inversely correlated with  COX-2  or the above microRNAs in  COX-2 -divergent breast cancer cell lines. CPEB2KO MCF10A cells exhibited oncogenic properties including increased proliferation, migration, invasion, EMT (decreased E-Cadherin, increased Vimentin, N-Cadherin, SNAI1, and ZEB1) and SLC phenotype (increased tumorsphere formation and SLC marker-expression). Tumor-suppressor p53 protein was shown to be a novel translationally-regulated target of CPEB2, validated with polysome profiling. CPEB2KO, but not wild-type cells produced lung colonies upon intravenous injection and subcutaneous tumors and spontaneous lung metastases upon implantation at mammary sites in NOD/SCID/IL2Rϒ-null mice, identified with HLA immunostaining. Similarly, siRNA-mediated  CPEB2  knockdown in MCF7 cells promoted oncogenic properties in vitro .  Human breast cancer tissues ( n  = 105) revealed a lower mRNA expression for  CPEB2  isoform A and also a lower A/B isoform ratio than in non-tumour breast tissues ( n  = 20), suggesting that CPEB2A accounts for the tumor-suppressor functions of CPEB2.    Conclusions  CPEB2, presumably the isoform A, plays a key role in suppressing tumorigenesis in mammary epithelial cells by repressing EMT, migration, invasion, proliferation and SLC phenotype, via multiple targets, including a newly-identified translational target p53.    Electronic supplementary material  The online version of this article (10.1186/s12885-019-5771-5) contains supplementary material, which is available to authorized users.

Tumor suppressor role of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in human mammary epithelial cells