Abstract
Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.
Highlights
Mammary epithelial stem cells are fundamental to maintain tissue integrity
Pin1 and Fbxw7a control Notch1/4-dependent stem cell selfrenewal and frequency in an antagonistic fashion Having dissected the biochemistry of the Pin1/Fbxw7a antagonism in the Notch pathway, we investigated the impact of this interplay on the stem cell functions of Notch signaling in breast cancer cells
We have shown that stem cell and epithelialmesenchymal transition (EMT) markers are subjected to Pin1 levels, providing a molecular basis for the observed phenotypes
Summary
Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. We show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin. Following interaction with Pin, Notch and Notch, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7a. We show that Fbxw7a acts as an essential negative regulator of breast CSCs’ expansion by restraining Notch activity, but the establishment of a Notch/Pin active circuitry opposes this effect, promoting breast CSCs selfrenewal, tumor growth and metastasis in vivo. Suppression of Pin holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
