Mammary stem cells and breast cancer--role of Notch signalling.
Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44+/CD24- and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A gamma-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.
Farnie
Gillian
G
Breast Biology Group, Division of Cancer Studies, Faculty of Medicine and Human Sciences, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M20 4BX, UK.
Clarke
Robert B
RB
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051927:CD24 Antigen / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases