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Luminal progenitor and fetal mammary stem cell expression features predict breast tumor response to neoadjuvant chemotherapy.

Pfefferle AD, Spike BT, Wahl GM, Perou CM - Breast Cancer Res. Treat. (2015)

Bottom Line: Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas.We found that both human luminal progenitor and mouse fetal mammary stem cell features predicted pCR sensitivity across all breast cancer patients even after controlling for intrinsic subtype, proliferation, and clinical variables.This work identifies new clinically relevant gene signatures and highlights the value of a developmental biology perspective for uncovering relationships between tumor subtypes and their potential normal cellular counterparts.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA, adamp@email.unc.edu.

ABSTRACT
Mammary gland morphology and physiology are supported by an underlying cellular differentiation hierarchy. Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas. Investigating the normal cellular developmental phenotypes in breast tumors may provide new prognostic paradigms, identify new targetable pathways, and explain breast cancer subtype etiology. We used transcriptomic profiles coming from fluorescence-activated cell sorted (FACS) normal mammary epithelial cell types from several independent human and murine studies. Using a meta-analysis approach, we derived consensus gene signatures for both species and used these to relate tumors to normal mammary epithelial cell phenotypes. We then compiled a dataset of breast cancer patients treated with neoadjuvant anthracycline and taxane chemotherapy regimens to determine if normal cellular traits predict the likelihood of a pathological complete response (pCR) in a multivariate logistic regression analysis with clinical markers and genomic features such as cell proliferation. Most human and murine tumor subtypes shared some, but not all, features with a specific FACS-purified normal cell type; thus for most tumors a potential distinct cell type of 'origin' could be assigned. We found that both human luminal progenitor and mouse fetal mammary stem cell features predicted pCR sensitivity across all breast cancer patients even after controlling for intrinsic subtype, proliferation, and clinical variables. This work identifies new clinically relevant gene signatures and highlights the value of a developmental biology perspective for uncovering relationships between tumor subtypes and their potential normal cellular counterparts.

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Comparison of mammary subpopulations across studies. a Unsupervised hierarchical clustering was performed with the normal human mammary subpopulation dataset using any gene that had a log2 absolute expression value greater than three in at least four samples. b Pearson correlations were determined between the average expressions of each study’s subpopulations using all genes. c The first three principle components were determined across the human mammary subpopulation dataset
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Fig2: Comparison of mammary subpopulations across studies. a Unsupervised hierarchical clustering was performed with the normal human mammary subpopulation dataset using any gene that had a log2 absolute expression value greater than three in at least four samples. b Pearson correlations were determined between the average expressions of each study’s subpopulations using all genes. c The first three principle components were determined across the human mammary subpopulation dataset

Mentions: Following DWD normalization [26], an unsupervised cluster of the most variably expressed genes was performed using Gene Cluster v3.0 by selecting all genes with an absolute log2 expression value greater than three in at least four samples (212 genes) (Fig. 2a). In general, the four major array dendrogram nodes correspond to the four FACS-enriched mammary subpopulations, indicating that the most highly and variably expressed genes are similarly expressed across the different studies. Even when using all genes in the dataset, there is a high Pearson correlation within a given subpopulation across studies and low correlations to other subpopulations (Fig. 2b).Fig. 2


Luminal progenitor and fetal mammary stem cell expression features predict breast tumor response to neoadjuvant chemotherapy.

Pfefferle AD, Spike BT, Wahl GM, Perou CM - Breast Cancer Res. Treat. (2015)

Comparison of mammary subpopulations across studies. a Unsupervised hierarchical clustering was performed with the normal human mammary subpopulation dataset using any gene that had a log2 absolute expression value greater than three in at least four samples. b Pearson correlations were determined between the average expressions of each study’s subpopulations using all genes. c The first three principle components were determined across the human mammary subpopulation dataset
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4308649&req=5

Fig2: Comparison of mammary subpopulations across studies. a Unsupervised hierarchical clustering was performed with the normal human mammary subpopulation dataset using any gene that had a log2 absolute expression value greater than three in at least four samples. b Pearson correlations were determined between the average expressions of each study’s subpopulations using all genes. c The first three principle components were determined across the human mammary subpopulation dataset
Mentions: Following DWD normalization [26], an unsupervised cluster of the most variably expressed genes was performed using Gene Cluster v3.0 by selecting all genes with an absolute log2 expression value greater than three in at least four samples (212 genes) (Fig. 2a). In general, the four major array dendrogram nodes correspond to the four FACS-enriched mammary subpopulations, indicating that the most highly and variably expressed genes are similarly expressed across the different studies. Even when using all genes in the dataset, there is a high Pearson correlation within a given subpopulation across studies and low correlations to other subpopulations (Fig. 2b).Fig. 2

Bottom Line: Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas.We found that both human luminal progenitor and mouse fetal mammary stem cell features predicted pCR sensitivity across all breast cancer patients even after controlling for intrinsic subtype, proliferation, and clinical variables.This work identifies new clinically relevant gene signatures and highlights the value of a developmental biology perspective for uncovering relationships between tumor subtypes and their potential normal cellular counterparts.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA, adamp@email.unc.edu.

ABSTRACT
Mammary gland morphology and physiology are supported by an underlying cellular differentiation hierarchy. Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas. Investigating the normal cellular developmental phenotypes in breast tumors may provide new prognostic paradigms, identify new targetable pathways, and explain breast cancer subtype etiology. We used transcriptomic profiles coming from fluorescence-activated cell sorted (FACS) normal mammary epithelial cell types from several independent human and murine studies. Using a meta-analysis approach, we derived consensus gene signatures for both species and used these to relate tumors to normal mammary epithelial cell phenotypes. We then compiled a dataset of breast cancer patients treated with neoadjuvant anthracycline and taxane chemotherapy regimens to determine if normal cellular traits predict the likelihood of a pathological complete response (pCR) in a multivariate logistic regression analysis with clinical markers and genomic features such as cell proliferation. Most human and murine tumor subtypes shared some, but not all, features with a specific FACS-purified normal cell type; thus for most tumors a potential distinct cell type of 'origin' could be assigned. We found that both human luminal progenitor and mouse fetal mammary stem cell features predicted pCR sensitivity across all breast cancer patients even after controlling for intrinsic subtype, proliferation, and clinical variables. This work identifies new clinically relevant gene signatures and highlights the value of a developmental biology perspective for uncovering relationships between tumor subtypes and their potential normal cellular counterparts.

Show MeSH
Related in: MedlinePlus