title: Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast.
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.
authors.affiliation: Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rustighi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zannini
authors.forename: Luca
authors.initials: L
authors.lastname: Tiberi
authors.forename: Roberta
authors.initials: R
authors.lastname: Sommaggio
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sorrentino
authors.forename: Simona
authors.initials: S
authors.lastname: Nuzzo
authors.forename: Antonella
authors.initials: A
authors.lastname: Tuscano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Eterno
authors.forename: Federica
authors.initials: F
authors.lastname: Benvenuti
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D044767:Ubiquitin-Protein Ligases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse