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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.

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.

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Related in: MedlinePlus

Embryonic mammary bud epithelial cells share key marker profiles with Brca1-/- and basal-like breast cancers. Many E12.5-stage embryonic mammary bud epithelial cells display a triple-negative profile. Immunofluorescence (IF) with ERα shows stain throughout the mammary mesenchymal tissue and no epithelial stain. IF with PR shows no staining of either mammary epithelial or mesenchymal cells. Control tissue shows staining in some luminal mammary epithelial cells in postnatal tissue. Erbb2 is expressed at low to moderate levels by some embryonic mammary epithelial cells, whereas other cells do not stain. Krt5 and Krt14 are highly expressed by many, but not all, embryonic mammary epithelial cells. All embryonic mammary epithelial cells express p63; many express low to moderate levels of Egfr. Scale bar, 50 μm.
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Figure 1: Embryonic mammary bud epithelial cells share key marker profiles with Brca1-/- and basal-like breast cancers. Many E12.5-stage embryonic mammary bud epithelial cells display a triple-negative profile. Immunofluorescence (IF) with ERα shows stain throughout the mammary mesenchymal tissue and no epithelial stain. IF with PR shows no staining of either mammary epithelial or mesenchymal cells. Control tissue shows staining in some luminal mammary epithelial cells in postnatal tissue. Erbb2 is expressed at low to moderate levels by some embryonic mammary epithelial cells, whereas other cells do not stain. Krt5 and Krt14 are highly expressed by many, but not all, embryonic mammary epithelial cells. All embryonic mammary epithelial cells express p63; many express low to moderate levels of Egfr. Scale bar, 50 μm.

Mentions: Midgestation embryonic mammary bud epithelial (MBE) cells are ER-, PR- and express low to moderate levels of Erbb2 (Figure 1). Many MBE cells express high levels of basal keratins (Krt5, Krt14), Egfr, and all express p63 (Figure 1). MBE cells exhibit marker profiles similar to those used to describe the defining features of triple-negative and basal-like breast cancers and may use similar signaling pathways and networks to underpin key biologic properties of similar cell types found enriched within both populations.


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 bud epithelial cells share key marker profiles with Brca1-/- and basal-like breast cancers. Many E12.5-stage embryonic mammary bud epithelial cells display a triple-negative profile. Immunofluorescence (IF) with ERα shows stain throughout the mammary mesenchymal tissue and no epithelial stain. IF with PR shows no staining of either mammary epithelial or mesenchymal cells. Control tissue shows staining in some luminal mammary epithelial cells in postnatal tissue. Erbb2 is expressed at low to moderate levels by some embryonic mammary epithelial cells, whereas other cells do not stain. Krt5 and Krt14 are highly expressed by many, but not all, embryonic mammary epithelial cells. All embryonic mammary epithelial cells express p63; many express low to moderate levels of Egfr. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672751&req=5

Figure 1: Embryonic mammary bud epithelial cells share key marker profiles with Brca1-/- and basal-like breast cancers. Many E12.5-stage embryonic mammary bud epithelial cells display a triple-negative profile. Immunofluorescence (IF) with ERα shows stain throughout the mammary mesenchymal tissue and no epithelial stain. IF with PR shows no staining of either mammary epithelial or mesenchymal cells. Control tissue shows staining in some luminal mammary epithelial cells in postnatal tissue. Erbb2 is expressed at low to moderate levels by some embryonic mammary epithelial cells, whereas other cells do not stain. Krt5 and Krt14 are highly expressed by many, but not all, embryonic mammary epithelial cells. All embryonic mammary epithelial cells express p63; many express low to moderate levels of Egfr. Scale bar, 50 μm.
Mentions: Midgestation embryonic mammary bud epithelial (MBE) cells are ER-, PR- and express low to moderate levels of Erbb2 (Figure 1). Many MBE cells express high levels of basal keratins (Krt5, Krt14), Egfr, and all express p63 (Figure 1). MBE cells exhibit marker profiles similar to those used to describe the defining features of triple-negative and basal-like breast cancers and may use similar signaling pathways and networks to underpin key biologic properties of similar cell types found enriched within both populations.

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