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Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.

Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW - PLoS ONE (2013)

Bottom Line: Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer.It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations.These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics and Information Technology, Bethesda, Maryland, United States of America.

ABSTRACT
Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

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Related in: MedlinePlus

Cytokeratin staining of a representative MOLF basal-like tumors.A) Keratin 5 staining. Positive cells were observed in normal ducts (black arrow) but only occasionally within the tumor mass (red arrow). B) Keratin 8 staining demonstrated heterogeneous staining across tumor samples.
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pone-0072287-g005: Cytokeratin staining of a representative MOLF basal-like tumors.A) Keratin 5 staining. Positive cells were observed in normal ducts (black arrow) but only occasionally within the tumor mass (red arrow). B) Keratin 8 staining demonstrated heterogeneous staining across tumor samples.

Mentions: To determine whether the genetic background of the tumors influenced the expression of standard clinical immunohistochemical markers as well as PAM50-defined intrinsic subtypes staining of tumors was performed. Three representative tumors clustering with human basal or luminal A subtypes from the MOLF cross were stained for estrogen or progesterone receptor, Ki67, Her2, the basal cytokeratin marker keratin 5 and the luminal cytokeratin 8. Basal cytokeratin 5 staining was restricted to the basal cells in the normal ducts, with occasional positive cells observed within tumor masses (figure 5A) in all tumors. Heterogeneity of luminal cytokeratin 8 was seen in all tumors, with focal regions of high expression observed in all tumors (figure 5B). Ki67 and Her2 staining was observed throughout all of the samples regardless of subtype prediction. As anticipated from previous studies, no ER or PR staining was observed in any of the tumor samples (data not shown).


Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.

Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW - PLoS ONE (2013)

Cytokeratin staining of a representative MOLF basal-like tumors.A) Keratin 5 staining. Positive cells were observed in normal ducts (black arrow) but only occasionally within the tumor mass (red arrow). B) Keratin 8 staining demonstrated heterogeneous staining across tumor samples.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756056&req=5

pone-0072287-g005: Cytokeratin staining of a representative MOLF basal-like tumors.A) Keratin 5 staining. Positive cells were observed in normal ducts (black arrow) but only occasionally within the tumor mass (red arrow). B) Keratin 8 staining demonstrated heterogeneous staining across tumor samples.
Mentions: To determine whether the genetic background of the tumors influenced the expression of standard clinical immunohistochemical markers as well as PAM50-defined intrinsic subtypes staining of tumors was performed. Three representative tumors clustering with human basal or luminal A subtypes from the MOLF cross were stained for estrogen or progesterone receptor, Ki67, Her2, the basal cytokeratin marker keratin 5 and the luminal cytokeratin 8. Basal cytokeratin 5 staining was restricted to the basal cells in the normal ducts, with occasional positive cells observed within tumor masses (figure 5A) in all tumors. Heterogeneity of luminal cytokeratin 8 was seen in all tumors, with focal regions of high expression observed in all tumors (figure 5B). Ki67 and Her2 staining was observed throughout all of the samples regardless of subtype prediction. As anticipated from previous studies, no ER or PR staining was observed in any of the tumor samples (data not shown).

Bottom Line: Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer.It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations.These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics and Information Technology, Bethesda, Maryland, United States of America.

ABSTRACT
Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

Show MeSH
Related in: MedlinePlus