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Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers.

Zvelebil M, Oliemuller E, Gao Q, Wansbury O, Mackay A, Kendrick H, Smalley MJ, Reis-Filho JS, Howard BA - Breast Cancer Res. (2013)

Bottom Line: Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells.Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors.

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ABSTRACT

Introduction: Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.

Methods: We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.

Results: Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.

Conclusions: Specific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.

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Embryonic mammary transcription factors are highly expressed in some Brca1-/- mammary tumor cells. (A) qRT-PCR data confirming embryonic-enriched expression of several basal-like tumor-associated transcription factors when compared with postnatal MEC subpopulations (described in [10] and [13]). MP, mammary primordium; MBE, E12.5-stage mammary bud epithelium; MM, E12.5-stage mammary mesenchyme; FB, fibroblast; ER-, luminal estrogen receptor negative; ER+, luminal estrogen-receptor positive; MYO, myoepithelial. (B) IHC showing cell types expressing embryonic mammary marker, Sox11 (guinea-pig antiserum) within embryonic mammary primordium. (C) IHC showing low level of Sox11 expression (guinea-pig antiserum) within 10-week-old postnatal mammary gland. (D-G) IHC showing Sox11 expression (guinea-pig antiserum) in some, but not all, Brca1-/- tumors. Scale bar, 50 μm.
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Figure 5: Embryonic mammary transcription factors are highly expressed in some Brca1-/- mammary tumor cells. (A) qRT-PCR data confirming embryonic-enriched expression of several basal-like tumor-associated transcription factors when compared with postnatal MEC subpopulations (described in [10] and [13]). MP, mammary primordium; MBE, E12.5-stage mammary bud epithelium; MM, E12.5-stage mammary mesenchyme; FB, fibroblast; ER-, luminal estrogen receptor negative; ER+, luminal estrogen-receptor positive; MYO, myoepithelial. (B) IHC showing cell types expressing embryonic mammary marker, Sox11 (guinea-pig antiserum) within embryonic mammary primordium. (C) IHC showing low level of Sox11 expression (guinea-pig antiserum) within 10-week-old postnatal mammary gland. (D-G) IHC showing Sox11 expression (guinea-pig antiserum) in some, but not all, Brca1-/- tumors. Scale bar, 50 μm.

Mentions: BCL11A, SOX11, and TPX2 showed consistent upregulation at an average of twofold or greater in ER- breast cancers across datasets (Figure 4A, B; Additional file 17) [16,38-43]. SOX11 and TPX2 showed consistent upregulation of twofold or greater in PR- breast cancers across datasets (Figure 4C; Additional file 17) [16,39,41-46]. SOX11 levels were consistently twofold higher in HER2+ versus HER2- samples across datasets [16,40,42,47-49] (Figure 4D and Additional file 18). SOX11 levels were higher in basal-like and HER2+ breast cancers compared with other subtypes (Figure 5E). BCL11A levels were consistently higher in basal-like breast cancers compared with other subtypes (Figure 4E). Both SOX11 and TPX2 showed a trend of increased expression levels with increasing tumor grade, whereas BCL11A did not (Figure 4F; Additional file 19). B3GNT5 levels tended to be higher in both ER-negative and PR-negative tumors. No significant association of PTDSS1 with ER- , PR-, HER2- status, or histologic grade was found.


Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers.

Zvelebil M, Oliemuller E, Gao Q, Wansbury O, Mackay A, Kendrick H, Smalley MJ, Reis-Filho JS, Howard BA - Breast Cancer Res. (2013)

Embryonic mammary transcription factors are highly expressed in some Brca1-/- mammary tumor cells. (A) qRT-PCR data confirming embryonic-enriched expression of several basal-like tumor-associated transcription factors when compared with postnatal MEC subpopulations (described in [10] and [13]). MP, mammary primordium; MBE, E12.5-stage mammary bud epithelium; MM, E12.5-stage mammary mesenchyme; FB, fibroblast; ER-, luminal estrogen receptor negative; ER+, luminal estrogen-receptor positive; MYO, myoepithelial. (B) IHC showing cell types expressing embryonic mammary marker, Sox11 (guinea-pig antiserum) within embryonic mammary primordium. (C) IHC showing low level of Sox11 expression (guinea-pig antiserum) within 10-week-old postnatal mammary gland. (D-G) IHC showing Sox11 expression (guinea-pig antiserum) in some, but not all, Brca1-/- tumors. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Embryonic mammary transcription factors are highly expressed in some Brca1-/- mammary tumor cells. (A) qRT-PCR data confirming embryonic-enriched expression of several basal-like tumor-associated transcription factors when compared with postnatal MEC subpopulations (described in [10] and [13]). MP, mammary primordium; MBE, E12.5-stage mammary bud epithelium; MM, E12.5-stage mammary mesenchyme; FB, fibroblast; ER-, luminal estrogen receptor negative; ER+, luminal estrogen-receptor positive; MYO, myoepithelial. (B) IHC showing cell types expressing embryonic mammary marker, Sox11 (guinea-pig antiserum) within embryonic mammary primordium. (C) IHC showing low level of Sox11 expression (guinea-pig antiserum) within 10-week-old postnatal mammary gland. (D-G) IHC showing Sox11 expression (guinea-pig antiserum) in some, but not all, Brca1-/- tumors. Scale bar, 50 μm.
Mentions: BCL11A, SOX11, and TPX2 showed consistent upregulation at an average of twofold or greater in ER- breast cancers across datasets (Figure 4A, B; Additional file 17) [16,38-43]. SOX11 and TPX2 showed consistent upregulation of twofold or greater in PR- breast cancers across datasets (Figure 4C; Additional file 17) [16,39,41-46]. SOX11 levels were consistently twofold higher in HER2+ versus HER2- samples across datasets [16,40,42,47-49] (Figure 4D and Additional file 18). SOX11 levels were higher in basal-like and HER2+ breast cancers compared with other subtypes (Figure 5E). BCL11A levels were consistently higher in basal-like breast cancers compared with other subtypes (Figure 4E). Both SOX11 and TPX2 showed a trend of increased expression levels with increasing tumor grade, whereas BCL11A did not (Figure 4F; Additional file 19). B3GNT5 levels tended to be higher in both ER-negative and PR-negative tumors. No significant association of PTDSS1 with ER- , PR-, HER2- status, or histologic grade was found.

Bottom Line: Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells.Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Cancer is often suggested to result from development gone awry. Links between normal embryonic development and cancer biology have been postulated, but no defined genetic basis has been established. We recently published the first transcriptomic analysis of embryonic mammary cell populations. Embryonic mammary epithelial cells are an immature progenitor cell population, lacking differentiation markers, which is reflected in their very distinct genetic profiles when compared with those of their postnatal descendents.

Methods: We defined an embryonic mammary epithelial signature that incorporates the most highly expressed genes from embryonic mammary epithelium when compared with the postnatal mammary epithelial cells. We looked for activation of the embryonic mammary epithelial signature in mouse mammary tumors that formed in mice in which Brca1 had been conditionally deleted from the mammary epithelium and in human breast cancers to determine whether any genetic links exist between embryonic mammary cells and breast cancers.

Results: Small subsets of the embryonic mammary epithelial signature were consistently activated in mouse Brca1-/- tumors and human basal-like breast cancers, which encoded predominantly transcriptional regulators, cell-cycle, and actin cytoskeleton components. Other embryonic gene subsets were found activated in non-basal-like tumor subtypes and repressed in basal-like tumors, including regulators of neuronal differentiation, transcription, and cell biosynthesis. Several embryonic genes showed significant upregulation in estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and/or grade 3 breast cancers. Among them, the transcription factor, SOX11, a progenitor cell and lineage regulator of nonmammary cell types, is found highly expressed in some Brca1-/- mammary tumors. By using RNA interference to silence SOX11 expression in breast cancer cells, we found evidence that SOX11 regulates breast cancer cell proliferation and cell survival.

Conclusions: Specific subsets of embryonic mammary genes, rather than the entire embryonic development transcriptomic program, are activated in tumorigenesis. Genes involved in embryonic mammary development are consistently upregulated in some breast cancers and warrant further investigation, potentially in drug-discovery research endeavors.

Show MeSH
Related in: MedlinePlus