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Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization.

Sabatier R, Finetti P, Guille A, Adelaide J, Chaffanet M, Viens P, Birnbaum D, Bertucci F - Mol. Cancer (2014)

Bottom Line: We provide a comprehensive characterization of the largest series of CL samples reported so far.Many differences exist between CL and the other subtypes, notably basal.An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Marseille, France. bertuccif@ipc.unicancer.fr.

ABSTRACT

Background: The lastly identified claudin-low (CL) subtype of breast cancer (BC) remains poorly described as compared to the other molecular subtypes. We provide a comprehensive characterization of the largest series of CL samples reported so far.

Methods: From a data set of 5447 invasive BC profiled using DNA microarrays, we identified 673 CL samples (12,4%) that we describe comparatively to the other molecular subtypes at several levels: clinicopathological, genomic, transcriptional, survival, and response to chemotherapy.

Results: CL samples display profiles different from other subtypes. For example, they differ from basal tumors regarding the hormone receptor status, with a lower frequency of triple negative (TN) tumors (52% vs 76% for basal cases). Like basal tumors, they show high genomic instability with many gains and losses. At the transcriptional level, CL tumors are the most undifferentiated tumors along the mammary epithelial hierarchy. Compared to basal tumors, they show enrichment for epithelial-to-mesenchymal transition markers, immune response genes, and cancer stem cell-like features, and higher activity of estrogen receptor (ER), progesterone receptor (PR), EGFR, SRC and TGFβ pathways, but lower activity of MYC and PI3K pathways. The 5-year disease-free survival of CL cases (67%) and the rate of pathological complete response (pCR) to primary chemotherapy (32%) are close to those of poor-prognosis and good responder subtypes (basal and ERBB2-enriched). However, the prognostic features of CL tumors are closer to those observed in the whole BC series and in the luminal A subtype, including proliferation-related gene expression signatures (GES). Immunity-related GES valuable in basal breast cancers are not significant in CL tumors. By contrast, the GES predictive for pCR in CL tumors resemble more to those of basal and HER2-enriched tumors than to those of luminal A tumors.

Conclusions: Many differences exist between CL and the other subtypes, notably basal. An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes.

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Related in: MedlinePlus

Comparison of gene expression signatures across molecular subtypes. Box plots of expression metagenes and scores across molecular subtypes: luminal, proliferation, immune, and core-EMT metagenes, differentiation score (mL, mature luminal; pL, porogenitor luminal; MaSC, mammary stem cells), stem cells score. P-values (t-test) of comparisons between CL and each of the other subtypes are shown as follows: *, ≤5%; **, ≤1%; ***, ≤0.1%.
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Fig2: Comparison of gene expression signatures across molecular subtypes. Box plots of expression metagenes and scores across molecular subtypes: luminal, proliferation, immune, and core-EMT metagenes, differentiation score (mL, mature luminal; pL, porogenitor luminal; MaSC, mammary stem cells), stem cells score. P-values (t-test) of comparisons between CL and each of the other subtypes are shown as follows: *, ≤5%; **, ≤1%; ***, ≤0.1%.

Mentions: We compared the mRNA expression of different genes and pathways in CL versus other subtypes. As expected, CL tumors showed low expression of ESR1, PGR and ERBB2 genes (Table 1) and low expression of associated genes as demonstrated by the low expression of the luminal metagene (Figure 2) and the ER, PR and ERBB2 activation pathways signatures (Additional file 4: Figure S1). Regarding these genes and signatures, significant differences existed between CL and the other subtypes, including the basal subtype. CL BCs also differed from basal BCs in other aspects. Expression of the proliferation-related metagene in CL tumors was lower than in basal tumors, but higher than in luminal A and normal-like tumors (Figure 2 and Additional file 5: Table S3). CL tumors displayed lower expression of MYC, PI3K, and β-catenin activation pathways when compared to basal cases, with activity levels close to those of luminal A tumors for MYC and PI3K (Additional file 4: Figure S1). By contrast, they showed higher expression than basal tumors of EGFR, SRC, TGFβ and STAT3 activation pathways. We also analyzed the expression of immune response GES [42]. CL tumors overexpressed T-cells, B-cells and granulocytes metagenes as compared to the other subtypes (Figure 2). They also highly expressed the IFNγ activation pathway with similar level than that of basal cases (Additional file 4: Figure S1).Figure 2


Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization.

Sabatier R, Finetti P, Guille A, Adelaide J, Chaffanet M, Viens P, Birnbaum D, Bertucci F - Mol. Cancer (2014)

Comparison of gene expression signatures across molecular subtypes. Box plots of expression metagenes and scores across molecular subtypes: luminal, proliferation, immune, and core-EMT metagenes, differentiation score (mL, mature luminal; pL, porogenitor luminal; MaSC, mammary stem cells), stem cells score. P-values (t-test) of comparisons between CL and each of the other subtypes are shown as follows: *, ≤5%; **, ≤1%; ***, ≤0.1%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197217&req=5

Fig2: Comparison of gene expression signatures across molecular subtypes. Box plots of expression metagenes and scores across molecular subtypes: luminal, proliferation, immune, and core-EMT metagenes, differentiation score (mL, mature luminal; pL, porogenitor luminal; MaSC, mammary stem cells), stem cells score. P-values (t-test) of comparisons between CL and each of the other subtypes are shown as follows: *, ≤5%; **, ≤1%; ***, ≤0.1%.
Mentions: We compared the mRNA expression of different genes and pathways in CL versus other subtypes. As expected, CL tumors showed low expression of ESR1, PGR and ERBB2 genes (Table 1) and low expression of associated genes as demonstrated by the low expression of the luminal metagene (Figure 2) and the ER, PR and ERBB2 activation pathways signatures (Additional file 4: Figure S1). Regarding these genes and signatures, significant differences existed between CL and the other subtypes, including the basal subtype. CL BCs also differed from basal BCs in other aspects. Expression of the proliferation-related metagene in CL tumors was lower than in basal tumors, but higher than in luminal A and normal-like tumors (Figure 2 and Additional file 5: Table S3). CL tumors displayed lower expression of MYC, PI3K, and β-catenin activation pathways when compared to basal cases, with activity levels close to those of luminal A tumors for MYC and PI3K (Additional file 4: Figure S1). By contrast, they showed higher expression than basal tumors of EGFR, SRC, TGFβ and STAT3 activation pathways. We also analyzed the expression of immune response GES [42]. CL tumors overexpressed T-cells, B-cells and granulocytes metagenes as compared to the other subtypes (Figure 2). They also highly expressed the IFNγ activation pathway with similar level than that of basal cases (Additional file 4: Figure S1).Figure 2

Bottom Line: We provide a comprehensive characterization of the largest series of CL samples reported so far.Many differences exist between CL and the other subtypes, notably basal.An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Centre de Recherche en Cancérologie de Marseille, UMR1068 Inserm, Institut Paoli-Calmettes (IPC), Marseille, France. bertuccif@ipc.unicancer.fr.

ABSTRACT

Background: The lastly identified claudin-low (CL) subtype of breast cancer (BC) remains poorly described as compared to the other molecular subtypes. We provide a comprehensive characterization of the largest series of CL samples reported so far.

Methods: From a data set of 5447 invasive BC profiled using DNA microarrays, we identified 673 CL samples (12,4%) that we describe comparatively to the other molecular subtypes at several levels: clinicopathological, genomic, transcriptional, survival, and response to chemotherapy.

Results: CL samples display profiles different from other subtypes. For example, they differ from basal tumors regarding the hormone receptor status, with a lower frequency of triple negative (TN) tumors (52% vs 76% for basal cases). Like basal tumors, they show high genomic instability with many gains and losses. At the transcriptional level, CL tumors are the most undifferentiated tumors along the mammary epithelial hierarchy. Compared to basal tumors, they show enrichment for epithelial-to-mesenchymal transition markers, immune response genes, and cancer stem cell-like features, and higher activity of estrogen receptor (ER), progesterone receptor (PR), EGFR, SRC and TGFβ pathways, but lower activity of MYC and PI3K pathways. The 5-year disease-free survival of CL cases (67%) and the rate of pathological complete response (pCR) to primary chemotherapy (32%) are close to those of poor-prognosis and good responder subtypes (basal and ERBB2-enriched). However, the prognostic features of CL tumors are closer to those observed in the whole BC series and in the luminal A subtype, including proliferation-related gene expression signatures (GES). Immunity-related GES valuable in basal breast cancers are not significant in CL tumors. By contrast, the GES predictive for pCR in CL tumors resemble more to those of basal and HER2-enriched tumors than to those of luminal A tumors.

Conclusions: Many differences exist between CL and the other subtypes, notably basal. An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes.

Show MeSH
Related in: MedlinePlus