Dissection of a stem cell hierarchy in the human breast

TY - BOOK

T1 - Dissection of a stem cell hierarchy in the human breast

AU - Rubner Fridriksdottir, Agla Jael

PY - 2008

Y1 - 2008

N2 - The human breast is a unique organ in that it undergoes most of its development after birth underthe control of systemic hormones. Throughout the reproductive life of women, the breast glandundergoes changes in morphogenesis as evidenced by continuous cell proliferation, differentiationand apoptosis during each menstrual cycle. These changes are most prominent during pregnancy,lactation and involution after breast feeding. These highly dynamic changes are thought to rely onthe presence of a breast epithelial stem cell population (reviewed in (Fridriksdottir et al. 2005)).Nevertheless, cellular pathways that contribute to adult human breast gland architecture and celllineages have not been described. Here, I identify a candidate stem cell niche in ducts, and zonescontaining progenitor cells in lobules (Villadsen and Fridriksdottir et al. 2007). Putative stem cellsresiding in ducts are essentially quiescent, whereas the progenitor cells in the lobules are latent oractively dividing. Cells from ducts and lobules are collected and functionally characterized bycolony formation on tissue culture plastic, mammosphere formation in suspension culture, andmorphogenesis in laminin-rich extracellular matrix gel. Staining for the epithelial lineage markers,cytokeratins K14 and K19, further reveals multipotent cells in the stem cell zone and three lineage-restricted cell types outside this zone. Multiparameter cell sorting and functional characterizationwith reference to anatomical sites in situ confirm this pattern. One of the lineage-restricted celltypes is a luminal epithelial progenitor, which prospectively can be highly enriched for by cellsorting with CDw75. This progenitor among other markers expresses the GATA-binding protein 3(GATA-3) transcription factor and endocrine receptors. The candidate stem cell on the other hand isenriched for in c-KIT-positive and Aldeflour-positive populations by fluorescent-activated cellsorting (FACS) analysis. That the four cell types are indeed constituents of a heretofore undescribedstem cell hierarchy is assessed in long-term cultures where senescence is bypassed. These findingsidentify an adult human breast ductal stem cell activity and the earliest descendants thereof. Furthercharacterization of the ductal stem cell niche, especially in terms of possible interaction withsurrounding stromal cells (Sigurdsson and Fridriksdottir et al. 2006) is highly warranted as thismay lead to identification of those long-term breast resident(s) that accumulate enough genetic hitsfor clonal expansion and tumor development, i.e. the cellular origin(s) of breast cancer.

AB - The human breast is a unique organ in that it undergoes most of its development after birth underthe control of systemic hormones. Throughout the reproductive life of women, the breast glandundergoes changes in morphogenesis as evidenced by continuous cell proliferation, differentiationand apoptosis during each menstrual cycle. These changes are most prominent during pregnancy,lactation and involution after breast feeding. These highly dynamic changes are thought to rely onthe presence of a breast epithelial stem cell population (reviewed in (Fridriksdottir et al. 2005)).Nevertheless, cellular pathways that contribute to adult human breast gland architecture and celllineages have not been described. Here, I identify a candidate stem cell niche in ducts, and zonescontaining progenitor cells in lobules (Villadsen and Fridriksdottir et al. 2007). Putative stem cellsresiding in ducts are essentially quiescent, whereas the progenitor cells in the lobules are latent oractively dividing. Cells from ducts and lobules are collected and functionally characterized bycolony formation on tissue culture plastic, mammosphere formation in suspension culture, andmorphogenesis in laminin-rich extracellular matrix gel. Staining for the epithelial lineage markers,cytokeratins K14 and K19, further reveals multipotent cells in the stem cell zone and three lineage-restricted cell types outside this zone. Multiparameter cell sorting and functional characterizationwith reference to anatomical sites in situ confirm this pattern. One of the lineage-restricted celltypes is a luminal epithelial progenitor, which prospectively can be highly enriched for by cellsorting with CDw75. This progenitor among other markers expresses the GATA-binding protein 3(GATA-3) transcription factor and endocrine receptors. The candidate stem cell on the other hand isenriched for in c-KIT-positive and Aldeflour-positive populations by fluorescent-activated cellsorting (FACS) analysis. That the four cell types are indeed constituents of a heretofore undescribedstem cell hierarchy is assessed in long-term cultures where senescence is bypassed. These findingsidentify an adult human breast ductal stem cell activity and the earliest descendants thereof. Furthercharacterization of the ductal stem cell niche, especially in terms of possible interaction withsurrounding stromal cells (Sigurdsson and Fridriksdottir et al. 2006) is highly warranted as thismay lead to identification of those long-term breast resident(s) that accumulate enough genetic hitsfor clonal expansion and tumor development, i.e. the cellular origin(s) of breast cancer.

M3 - Ph.D. thesis

BT - Dissection of a stem cell hierarchy in the human breast

PB - Museum Tusculanum

ER -