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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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Immature Mammary Lobules of Nulliparous Women or BRCA1/2 Mutation Carriers Are Enriched in ALDH1A1+ Cells(A) Comparison of percentage of ALDH1A1+ cells in all samples stratified on parity showed no significant difference between samples from iparous women and those from parous women. Bars represent mean percentages of ALDH1A1+ cells across the indicated number of samples ± SEM.(B and C) Comparison of percentage of ALDH1A1+ cells in all samples stratified on BRCA status showed no significant difference between samples from women with and without confirmed mutations in BRCA1 or BRCA2 (B). Analysis of individual lobules from 18 women showed a significant increase in ALDH1A1 representation in lobule type 1 in samples from BRCA1/2 mutation compared to samples from non-BRCA carriers (C). Bars represent mean percentage of ALDH1A1+ cells ± SEM.(D and E) Comparison of percentage of ALDH1A1+ cells in lobule types 1–3 in samples from women without (D) and with (E) BRCA1/2 mutations, respectively, showed a significantly higher percentage of ALDH1A1+ cells in lobule type 1 from iparous women compared to those from parous women in both BRCA carriers and non-carriers.(F) Comparison of mammosphere-forming ability in dissociated mammary epithelial cells from iparous and parous women, showing higher sphere formation in samples from the latter group. Analysis was done on samples from non-BRCA carriers.P values were calculated using Mann-Whitney U test (A, B, and F) or one-way ANOVA with Sidak’s multiple comparisons test (C–E).
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fig6: Immature Mammary Lobules of Nulliparous Women or BRCA1/2 Mutation Carriers Are Enriched in ALDH1A1+ Cells(A) Comparison of percentage of ALDH1A1+ cells in all samples stratified on parity showed no significant difference between samples from iparous women and those from parous women. Bars represent mean percentages of ALDH1A1+ cells across the indicated number of samples ± SEM.(B and C) Comparison of percentage of ALDH1A1+ cells in all samples stratified on BRCA status showed no significant difference between samples from women with and without confirmed mutations in BRCA1 or BRCA2 (B). Analysis of individual lobules from 18 women showed a significant increase in ALDH1A1 representation in lobule type 1 in samples from BRCA1/2 mutation compared to samples from non-BRCA carriers (C). Bars represent mean percentage of ALDH1A1+ cells ± SEM.(D and E) Comparison of percentage of ALDH1A1+ cells in lobule types 1–3 in samples from women without (D) and with (E) BRCA1/2 mutations, respectively, showed a significantly higher percentage of ALDH1A1+ cells in lobule type 1 from iparous women compared to those from parous women in both BRCA carriers and non-carriers.(F) Comparison of mammosphere-forming ability in dissociated mammary epithelial cells from iparous and parous women, showing higher sphere formation in samples from the latter group. Analysis was done on samples from non-BRCA carriers.P values were calculated using Mann-Whitney U test (A, B, and F) or one-way ANOVA with Sidak’s multiple comparisons test (C–E).

Mentions: To directly investigate possible correlations between the size of stem/progenitor cell population and parity, we compared the representation of ALDH1A1+ cells in the mammary epithelium of iparous women with that of parous women. We found no significant difference in the percentage of ALDH1A1+ cells in the epithelium of iparous women compared to that of parous women, when analyzing all the samples together (Figure 6A). Because the samples came from a heterogeneous patient population, we carried out the same analysis separately in samples from prophylactic mastectomy in BRCA1/2 mutation carriers and the rest of mammoplasty samples (non-BRCA). Overall there was a higher representation of ALDH1A1+ cells in the mammary epithelium of BRCA mutation carriers compared to non-carriers, but the difference was not statistically significant (Figure 6B). When analysis was performed separately for different lobule types, however, a significantly larger percentage of ALDH1A1+ cells was seen in L1 from BRCA1/2 mutation carriers compared to non-carriers (Figure 6C). Similarly, a considerable enrichment in ALDH1A1+ cells was seen in L1 from iparous women compared to parous women when BRCA1/2 mutation carriers and non-carriers were analyzed separately (Figures 6D and 6E). ALDH activity assessed by the ALDEFLUOR assay was not significantly different in samples from iparous and parous women, or in BRCA1/2 mutation carriers and non-carriers (data not shown), possibly due to the contribution of other isoforms to this activity (Honeth et al., 2014).


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)

Immature Mammary Lobules of Nulliparous Women or BRCA1/2 Mutation Carriers Are Enriched in ALDH1A1+ Cells(A) Comparison of percentage of ALDH1A1+ cells in all samples stratified on parity showed no significant difference between samples from iparous women and those from parous women. Bars represent mean percentages of ALDH1A1+ cells across the indicated number of samples ± SEM.(B and C) Comparison of percentage of ALDH1A1+ cells in all samples stratified on BRCA status showed no significant difference between samples from women with and without confirmed mutations in BRCA1 or BRCA2 (B). Analysis of individual lobules from 18 women showed a significant increase in ALDH1A1 representation in lobule type 1 in samples from BRCA1/2 mutation compared to samples from non-BRCA carriers (C). Bars represent mean percentage of ALDH1A1+ cells ± SEM.(D and E) Comparison of percentage of ALDH1A1+ cells in lobule types 1–3 in samples from women without (D) and with (E) BRCA1/2 mutations, respectively, showed a significantly higher percentage of ALDH1A1+ cells in lobule type 1 from iparous women compared to those from parous women in both BRCA carriers and non-carriers.(F) Comparison of mammosphere-forming ability in dissociated mammary epithelial cells from iparous and parous women, showing higher sphere formation in samples from the latter group. Analysis was done on samples from non-BRCA carriers.P values were calculated using Mann-Whitney U test (A, B, and F) or one-way ANOVA with Sidak’s multiple comparisons test (C–E).
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fig6: Immature Mammary Lobules of Nulliparous Women or BRCA1/2 Mutation Carriers Are Enriched in ALDH1A1+ Cells(A) Comparison of percentage of ALDH1A1+ cells in all samples stratified on parity showed no significant difference between samples from iparous women and those from parous women. Bars represent mean percentages of ALDH1A1+ cells across the indicated number of samples ± SEM.(B and C) Comparison of percentage of ALDH1A1+ cells in all samples stratified on BRCA status showed no significant difference between samples from women with and without confirmed mutations in BRCA1 or BRCA2 (B). Analysis of individual lobules from 18 women showed a significant increase in ALDH1A1 representation in lobule type 1 in samples from BRCA1/2 mutation compared to samples from non-BRCA carriers (C). Bars represent mean percentage of ALDH1A1+ cells ± SEM.(D and E) Comparison of percentage of ALDH1A1+ cells in lobule types 1–3 in samples from women without (D) and with (E) BRCA1/2 mutations, respectively, showed a significantly higher percentage of ALDH1A1+ cells in lobule type 1 from iparous women compared to those from parous women in both BRCA carriers and non-carriers.(F) Comparison of mammosphere-forming ability in dissociated mammary epithelial cells from iparous and parous women, showing higher sphere formation in samples from the latter group. Analysis was done on samples from non-BRCA carriers.P values were calculated using Mann-Whitney U test (A, B, and F) or one-way ANOVA with Sidak’s multiple comparisons test (C–E).
Mentions: To directly investigate possible correlations between the size of stem/progenitor cell population and parity, we compared the representation of ALDH1A1+ cells in the mammary epithelium of iparous women with that of parous women. We found no significant difference in the percentage of ALDH1A1+ cells in the epithelium of iparous women compared to that of parous women, when analyzing all the samples together (Figure 6A). Because the samples came from a heterogeneous patient population, we carried out the same analysis separately in samples from prophylactic mastectomy in BRCA1/2 mutation carriers and the rest of mammoplasty samples (non-BRCA). Overall there was a higher representation of ALDH1A1+ cells in the mammary epithelium of BRCA mutation carriers compared to non-carriers, but the difference was not statistically significant (Figure 6B). When analysis was performed separately for different lobule types, however, a significantly larger percentage of ALDH1A1+ cells was seen in L1 from BRCA1/2 mutation carriers compared to non-carriers (Figure 6C). Similarly, a considerable enrichment in ALDH1A1+ cells was seen in L1 from iparous women compared to parous women when BRCA1/2 mutation carriers and non-carriers were analyzed separately (Figures 6D and 6E). ALDH activity assessed by the ALDEFLUOR assay was not significantly different in samples from iparous and parous women, or in BRCA1/2 mutation carriers and non-carriers (data not shown), possibly due to the contribution of other isoforms to this activity (Honeth et al., 2014).

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