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Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule.

Honeth G, Schiavinotto T, Vaggi F, Marlow R, Kanno T, Shinomiya I, Lombardi S, Buchupalli B, Graham R, Gazinska P, Ramalingam V, Burchell J, Purushotham AD, Pinder SE, Csikasz-Nagy A, Dontu G - Stem Cell Reports (2015)

Bottom Line: However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known.In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals.An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of iparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers.

View Article: PubMed Central - PubMed

Affiliation: Research Oncology, King's College London School of Medicine, London SE1 9RT, UK. Electronic address: gabriella.honeth@med.lu.se.

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ALDH1A1+ Cells Are Predominantly Quiescent(A) Double immunostaining for ALDH1A1 (red) and MCM2 (brown) in normal breast epithelium showing that these markers are rarely co-localized in the same cells (left: arrow, ALDH1A1+ cells; arrowhead, MCM2+ cells). Rare ALDH1A1low cells positive for MCM2 can be detected (right: arrowhead). Representative examples from stainings of five different samples are shown.(B) Double IF stainings for ALDH1A1 and p27 showing co-localization of these markers. Representative example from stainings of six different samples is shown.(C) Consecutive sections from a mammoplasty sample showing ALDH1A1 (red) expressed at the distal end of a small growing lobule. Double stainings with MCM2 (left) and p27 (middle) confirm patterns seen in (A and B).Scale bar, 50 μm in (A and B) and 100 μm in (C).
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fig3: ALDH1A1+ Cells Are Predominantly Quiescent(A) Double immunostaining for ALDH1A1 (red) and MCM2 (brown) in normal breast epithelium showing that these markers are rarely co-localized in the same cells (left: arrow, ALDH1A1+ cells; arrowhead, MCM2+ cells). Rare ALDH1A1low cells positive for MCM2 can be detected (right: arrowhead). Representative examples from stainings of five different samples are shown.(B) Double IF stainings for ALDH1A1 and p27 showing co-localization of these markers. Representative example from stainings of six different samples is shown.(C) Consecutive sections from a mammoplasty sample showing ALDH1A1 (red) expressed at the distal end of a small growing lobule. Double stainings with MCM2 (left) and p27 (middle) confirm patterns seen in (A and B).Scale bar, 50 μm in (A and B) and 100 μm in (C).

Mentions: The areas where ALDH1A1 was expressed were characterized by a less organized bilayer structure, often with no clear lumen, co-localization of basal (CK14, CK5/6) and luminal (CK19) cytokeratins in the same cells (Figures 2A and S4), and often lower expression of EpCAM and CD10 (Figures S4 and 2I) compared to the surrounding epithelium. Further characterization using markers for proliferation (Ki67, MCM2) and cell-cycle arrest (p27) indicated that these areas were mainly resting or quiescent (Figure 3).


Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule.

Honeth G, Schiavinotto T, Vaggi F, Marlow R, Kanno T, Shinomiya I, Lombardi S, Buchupalli B, Graham R, Gazinska P, Ramalingam V, Burchell J, Purushotham AD, Pinder SE, Csikasz-Nagy A, Dontu G - Stem Cell Reports (2015)

ALDH1A1+ Cells Are Predominantly Quiescent(A) Double immunostaining for ALDH1A1 (red) and MCM2 (brown) in normal breast epithelium showing that these markers are rarely co-localized in the same cells (left: arrow, ALDH1A1+ cells; arrowhead, MCM2+ cells). Rare ALDH1A1low cells positive for MCM2 can be detected (right: arrowhead). Representative examples from stainings of five different samples are shown.(B) Double IF stainings for ALDH1A1 and p27 showing co-localization of these markers. Representative example from stainings of six different samples is shown.(C) Consecutive sections from a mammoplasty sample showing ALDH1A1 (red) expressed at the distal end of a small growing lobule. Double stainings with MCM2 (left) and p27 (middle) confirm patterns seen in (A and B).Scale bar, 50 μm in (A and B) and 100 μm in (C).
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fig3: ALDH1A1+ Cells Are Predominantly Quiescent(A) Double immunostaining for ALDH1A1 (red) and MCM2 (brown) in normal breast epithelium showing that these markers are rarely co-localized in the same cells (left: arrow, ALDH1A1+ cells; arrowhead, MCM2+ cells). Rare ALDH1A1low cells positive for MCM2 can be detected (right: arrowhead). Representative examples from stainings of five different samples are shown.(B) Double IF stainings for ALDH1A1 and p27 showing co-localization of these markers. Representative example from stainings of six different samples is shown.(C) Consecutive sections from a mammoplasty sample showing ALDH1A1 (red) expressed at the distal end of a small growing lobule. Double stainings with MCM2 (left) and p27 (middle) confirm patterns seen in (A and B).Scale bar, 50 μm in (A and B) and 100 μm in (C).
Mentions: The areas where ALDH1A1 was expressed were characterized by a less organized bilayer structure, often with no clear lumen, co-localization of basal (CK14, CK5/6) and luminal (CK19) cytokeratins in the same cells (Figures 2A and S4), and often lower expression of EpCAM and CD10 (Figures S4 and 2I) compared to the surrounding epithelium. Further characterization using markers for proliferation (Ki67, MCM2) and cell-cycle arrest (p27) indicated that these areas were mainly resting or quiescent (Figure 3).

Bottom Line: However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known.In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals.An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of iparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers.

View Article: PubMed Central - PubMed

Affiliation: Research Oncology, King's College London School of Medicine, London SE1 9RT, UK. Electronic address: gabriella.honeth@med.lu.se.

Show MeSH
Related in: MedlinePlus