Limits...
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.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.

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

Homo sapiens-enriched gene signatures. a HsEnriched gene signatures were identified for each mammary subpopulation. First, the overlap of genes highly expressed within each subpopulation across studies was determined. This overlapping gene set was further filtered to remove genes also identified as enriched in another subpopulation to limit the signature to genes specific to an individual subpopulation. The remaining genes comprised the HsEnriched gene signature for that subpopulation, as indicated by the shaded box. b The standardized average expression of the four HsEnriched gene signatures was calculated across three human datasets and displayed by intrinsic tumor subtype. c A nearest centroid predictor using the HsEnriched gene signatures was used to determine which epithelial features each tumor most represented. To reduce spurious findings, any tumor with a negative silhouette width was considered to have a weak association and was labeled as ‘unclassified’
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4308649&req=5

Fig3: Homo sapiens-enriched gene signatures. a HsEnriched gene signatures were identified for each mammary subpopulation. First, the overlap of genes highly expressed within each subpopulation across studies was determined. This overlapping gene set was further filtered to remove genes also identified as enriched in another subpopulation to limit the signature to genes specific to an individual subpopulation. The remaining genes comprised the HsEnriched gene signature for that subpopulation, as indicated by the shaded box. b The standardized average expression of the four HsEnriched gene signatures was calculated across three human datasets and displayed by intrinsic tumor subtype. c A nearest centroid predictor using the HsEnriched gene signatures was used to determine which epithelial features each tumor most represented. To reduce spurious findings, any tumor with a negative silhouette width was considered to have a weak association and was labeled as ‘unclassified’

Mentions: As shown in Fig. 2, there is a natural degree of variation between samples of a given subpopulation. We therefore developed gene signatures for each human mammary subpopulation by integrating consensus information across all three datasets (Table 1) to identify the highest confidence subpopulation-specific genes. First, genes highly expressed (FDR < 5 %) within each mammary subpopulation were found using a two-class (subpopulation X versus all others) SAM analysis [24] within each dataset [19–21]. Second, the overlap of genes highly expressed within a particular subpopulation across studies was determined. Lastly, as it is possible in the above analysis to have the same gene in the signature of more than one subpopulation, genes that were identified to be significantly associated with more than one subpopulation were also removed. This resulted in a single, consensus Homo sapiens-enriched (HsEnriched) signature per subpopulation (Fig. 3a). The average Euclidean distance was determined using a 10-fold cross validation for each normal mammary subpopulation sample to centroids created using either the HsEnriched-derived gene signatures or to centroids created using the gene signatures derived separately from each human study (Supplemental Fig. 1). The HsEnriched centroids had a significantly reduced Euclidean distance (~70 %) to each mammary subpopulation (t test p < 0.0001), indicating greater specificity for the consensus HsEnriched signatures when compared with any individual dataset’s subpopulation signature.Fig. 3


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)

Homo sapiens-enriched gene signatures. a HsEnriched gene signatures were identified for each mammary subpopulation. First, the overlap of genes highly expressed within each subpopulation across studies was determined. This overlapping gene set was further filtered to remove genes also identified as enriched in another subpopulation to limit the signature to genes specific to an individual subpopulation. The remaining genes comprised the HsEnriched gene signature for that subpopulation, as indicated by the shaded box. b The standardized average expression of the four HsEnriched gene signatures was calculated across three human datasets and displayed by intrinsic tumor subtype. c A nearest centroid predictor using the HsEnriched gene signatures was used to determine which epithelial features each tumor most represented. To reduce spurious findings, any tumor with a negative silhouette width was considered to have a weak association and was labeled as ‘unclassified’
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Homo sapiens-enriched gene signatures. a HsEnriched gene signatures were identified for each mammary subpopulation. First, the overlap of genes highly expressed within each subpopulation across studies was determined. This overlapping gene set was further filtered to remove genes also identified as enriched in another subpopulation to limit the signature to genes specific to an individual subpopulation. The remaining genes comprised the HsEnriched gene signature for that subpopulation, as indicated by the shaded box. b The standardized average expression of the four HsEnriched gene signatures was calculated across three human datasets and displayed by intrinsic tumor subtype. c A nearest centroid predictor using the HsEnriched gene signatures was used to determine which epithelial features each tumor most represented. To reduce spurious findings, any tumor with a negative silhouette width was considered to have a weak association and was labeled as ‘unclassified’
Mentions: As shown in Fig. 2, there is a natural degree of variation between samples of a given subpopulation. We therefore developed gene signatures for each human mammary subpopulation by integrating consensus information across all three datasets (Table 1) to identify the highest confidence subpopulation-specific genes. First, genes highly expressed (FDR < 5 %) within each mammary subpopulation were found using a two-class (subpopulation X versus all others) SAM analysis [24] within each dataset [19–21]. Second, the overlap of genes highly expressed within a particular subpopulation across studies was determined. Lastly, as it is possible in the above analysis to have the same gene in the signature of more than one subpopulation, genes that were identified to be significantly associated with more than one subpopulation were also removed. This resulted in a single, consensus Homo sapiens-enriched (HsEnriched) signature per subpopulation (Fig. 3a). The average Euclidean distance was determined using a 10-fold cross validation for each normal mammary subpopulation sample to centroids created using either the HsEnriched-derived gene signatures or to centroids created using the gene signatures derived separately from each human study (Supplemental Fig. 1). The HsEnriched centroids had a significantly reduced Euclidean distance (~70 %) to each mammary subpopulation (t test p < 0.0001), indicating greater specificity for the consensus HsEnriched signatures when compared with any individual dataset’s subpopulation signature.Fig. 3

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.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.

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