Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium

Iglesias, J. M. et al. (2015) Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium. PLoS ONE, 10(3), e0119718. (doi:10.1371/journal.pone.0119718) (PMID:25803307) (PMCID:PMC4372349)

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Abstract

We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. To better understand ANXA8’s association with this breast cancer subgroup we established ANXA8’s cellular distribution in the mammary gland and ANXA8’s effect on cell proliferation. We show that ANXA8 expression in the mouse mammary gland was strong during pre-puberty before the expansion of the rudimentary ductal network and was limited to a distinct subpopulation of ductal luminal epithelial cells but was not detected in TEB or in alveoli during pregnancy. Similarly, during late involution its expression was found in the surviving ductal epithelium, but not in the apoptotic alveoli. Double-immunofluorescence (IF) showed that ANXA8 positive (+ve) cells were ER-alpha negative (−ve) and mostly quiescent, as defined by lack of Ki67 expression during puberty and mid-pregnancy, but not terminally differentiated with ~15% of ANXA8 +ve cells re-entering the cell cycle at the start of pregnancy (day 4.5). RT-PCR on RNA from FACS-sorted cells and double-IF showed that ANXA8+ve cells were a subpopulation of c-kit +ve luminal progenitor cells, which have recently been identified as the cells of origin of basal-like breast cancers. Over expression of ANXA8 in the mammary epithelial cell line Kim-2 led to a G0/G1 arrest and suppressed Ki67 expression, indicating cell cycle exit. Our data therefore identify ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8’s association with their specific cells of origin.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McDonald, Dr Laura and Stein, Dr Torsten and Ferrier, Mr Roderick and Blyth, Professor Karen and Pringle, Mrs Marie and Iglesias, Dr Juan and Cairney, Dr Claire
Authors: Iglesias, J. M., Cairney, C. J., Ferrier, R. K., McDonald, L., Soady, K., Kendrick, H., Pringle, M.-A., Morgan, R. O., Martin, F., Smalley, M. J., Blyth, K., and Stein, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in PLoS ONE 10(3):e0119718
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
613551Annexin A8's role in progenitor cell maintenance within the cells of origin of basal-like breast cancers.Torsten SteinBreast Cancer Campaign (BR-CANCER)2012NovPR006ICS - EXPERIMENTAL THERAPEUTICS