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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.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.

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fMaSC-enriched gene signatures. a The univariate logistic regression odds ratio predicting pathologic complete response to neoadjuvant anthracycline and taxane chemotherapy was determined using a 702 patient dataset, with the 95 % confidence interval shown as a forest plot. A single ‘*’ indicates that the signature was univariate significant, while ‘***’ indicates that the signature was both univariate and multivariate significant (p < 0.05). b Pearson correlations of multivariate significant gene signatures and proliferation were determined. c The standardized average expression of the fMaSC-MmEnriched signature and its two refined signatures were calculated across three human datasets and displayed by intrinsic tumor subtype. d Genes in the fMaSC-MmEnriched-refined1 signature. e Genes in the fMaSC-MmEnriched-refined2 signature
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Fig5: fMaSC-enriched gene signatures. a The univariate logistic regression odds ratio predicting pathologic complete response to neoadjuvant anthracycline and taxane chemotherapy was determined using a 702 patient dataset, with the 95 % confidence interval shown as a forest plot. A single ‘*’ indicates that the signature was univariate significant, while ‘***’ indicates that the signature was both univariate and multivariate significant (p < 0.05). b Pearson correlations of multivariate significant gene signatures and proliferation were determined. c The standardized average expression of the fMaSC-MmEnriched signature and its two refined signatures were calculated across three human datasets and displayed by intrinsic tumor subtype. d Genes in the fMaSC-MmEnriched-refined1 signature. e Genes in the fMaSC-MmEnriched-refined2 signature

Mentions: Six normal mammary gene signatures were UVA and MVA significant (Supplemental Tables 3 and 4), with the 95 % UVA odds ratio of these six signatures and all other ‘enriched signatures’ displayed in Fig. 5a. Interestingly, the LumProg-HsEnriched and LumProg-HsEnriched-feature1 signatures, both of which were highly correlated (Fig. 5b), were significant in the UVA and MVA analyses, indicating that tumors with LumProg features are more likely to respond to neoadjuvant treatment. Importantly, this response was independent of proliferation, as highlighted by their low correlation to the PAM50-Proliferation gene signature (Fig. 5b).Fig. 5


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)

fMaSC-enriched gene signatures. a The univariate logistic regression odds ratio predicting pathologic complete response to neoadjuvant anthracycline and taxane chemotherapy was determined using a 702 patient dataset, with the 95 % confidence interval shown as a forest plot. A single ‘*’ indicates that the signature was univariate significant, while ‘***’ indicates that the signature was both univariate and multivariate significant (p < 0.05). b Pearson correlations of multivariate significant gene signatures and proliferation were determined. c The standardized average expression of the fMaSC-MmEnriched signature and its two refined signatures were calculated across three human datasets and displayed by intrinsic tumor subtype. d Genes in the fMaSC-MmEnriched-refined1 signature. e Genes in the fMaSC-MmEnriched-refined2 signature
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4308649&req=5

Fig5: fMaSC-enriched gene signatures. a The univariate logistic regression odds ratio predicting pathologic complete response to neoadjuvant anthracycline and taxane chemotherapy was determined using a 702 patient dataset, with the 95 % confidence interval shown as a forest plot. A single ‘*’ indicates that the signature was univariate significant, while ‘***’ indicates that the signature was both univariate and multivariate significant (p < 0.05). b Pearson correlations of multivariate significant gene signatures and proliferation were determined. c The standardized average expression of the fMaSC-MmEnriched signature and its two refined signatures were calculated across three human datasets and displayed by intrinsic tumor subtype. d Genes in the fMaSC-MmEnriched-refined1 signature. e Genes in the fMaSC-MmEnriched-refined2 signature
Mentions: Six normal mammary gene signatures were UVA and MVA significant (Supplemental Tables 3 and 4), with the 95 % UVA odds ratio of these six signatures and all other ‘enriched signatures’ displayed in Fig. 5a. Interestingly, the LumProg-HsEnriched and LumProg-HsEnriched-feature1 signatures, both of which were highly correlated (Fig. 5b), were significant in the UVA and MVA analyses, indicating that tumors with LumProg features are more likely to respond to neoadjuvant treatment. Importantly, this response was independent of proliferation, as highlighted by their low correlation to the PAM50-Proliferation gene signature (Fig. 5b).Fig. 5

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