Tumor and Stem Cell Biology Prolyl Isomerase Pin1 Acts Downstream of miR200c to Promote Cancer Stem–like Cell Traits in Breast Cancer

Breast cancer stem–like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapsebutdruggable targets in appropriate subsets of this cell populationhave yet tobe identified.Herewe identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial–mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC.Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mousemammary stem cells. In human cells, freshly isolated from reductionmammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC. Cancer Res; 74(13); 3603–16. 2014 AACR.