title: Targeting breast stem cells with the cancer preventive compounds curcumin and piperine.
abstract: The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor cells through the dysregulation or acquisition of self-renewal. In order to determine whether the dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and malignant breast stem cells, we examined the effects of these compounds on mammosphere formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt signaling. Mammosphere formation assays were performed after curcumin, piperine, and control treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells, selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at 5 microM and completely at 10 microM concentration in normal and malignant breast cells. There was no effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50% at 5 microM and completely at 10 microM. Curcumin and piperine separately, and in combination, inhibit breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds could be potential cancer preventive agents. Mammosphere formation assays may be a quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment can be a mechanistic biomarker for use in human clinical trials.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine and Comprehensive Cancer Center, University of Michigan, 2150 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA. mkakaral@umich.edu
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kakarala
authors.forename: Dean E
authors.initials: DE
authors.lastname: Brenner
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.forename: Connie
authors.initials: C
authors.lastname: Cheng
authors.forename: Karim
authors.initials: K
authors.lastname: Tazi
authors.forename: Christophe
authors.initials: C
authors.lastname: Ginestier
authors.forename: Suling
authors.initials: S
authors.lastname: Liu
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dontu
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000470:Alkaloids / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000008:administration & dosage; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010880:Piperidines / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D051153:Wnt Proteins; D000444:Aldehyde Dehydrogenase; D003474:Curcumin; C008922:piperine