Stem cell-related markers in primary breast cancers and associated metastatic lesions

Güler, Gülnur; Balcı, Serdar; Costinean, Stefan; Ussakli, Cigdem; Irkkan, Çiğdem; Süren, Di̇nç; Sarı, Ebru Karadağ; Altundağ, Kadri̇; Özışık, Yavuz; Jones, Spencer S.; Bacher, Jason; Shapiro, Charles L.; Huebner, Kay

doi:10.1038/modpathol.2012.37

Cited by 32 publications

(37 citation statements)

References 20 publications

(34 reference statements)

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“…Expression of vimentin was scored as follows: sections were scored from 0–3 where ‘0’ corresponds to lack of positive staining and ‘3’ represents the most intense staining. Scores were calculated as follows: average intensity of the stain (1–3) x average percentage of positive cells, as previously described [42]. …”

Section: Methodsmentioning

confidence: 99%

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microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

et al. 2014

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Triple Negative Breast Cancers (TNBC) is a heterogeneous disease at the molecular and clinical level with poor outcome. Molecular subclassification of TNBCs is essential for optimal use of current therapies and for development of new drugs. microRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance; investigation of their involvement in a TNBC cohort may reveal biomarkers for diagnosis and prognosis of TNBC. Here we stratified a large TNBC cohort into Core Basal (CB, EGFR and/or CK5, 6 positive) and five negative (5NP) if all markers are negative. We determined the complete miRNA expression profile and found a subset of miRNAs specifically deregulated in the two subclasses.We identified a 4-miRNA signature given by miR-155, miR-493, miR-30e and miR-27a expression levels, that allowed subdivision of TNBCs not only into CB and 5NP subgroups (sensitivity 0.75 and specificity 0.56; AUC=0.74) but also into high risk and low risk groups. We tested the diagnostic and prognostic performances of both the 5 IHC marker panel and the 4-miRNA expression signatures, which clearly identify worse outcome patients in the treated and untreated subcohorts. Both signatures have diagnostic and prognostic value, predicting outcomes of patient treatment with the two most commonly used chemotherapy regimens in TNBC: anthracycline or anthracycline plus taxanes. Further investigation of the patients' overall survival treated with these regimens show that regardless of IHC group subdivision, taxanes addition did not benefit patients, possibly due to miRNA driven taxanes resistance. TNBC subclassification based on the 5 IHC markers and on the miR-155, miR-493, miR-30e, miR-27a expression levels are powerful diagnostic tools. Treatment choice and new drug development should consider this new subtyping and miRNA expression signature in planning low toxicity, maximum efficacy therapies.

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Section: Methodsmentioning

confidence: 99%

“…CD24 (SN3b; Neomarkers) and CD44 (DF1485; Dako) expression was determined by double staining of tumor cells [42, 43]. …”

Section: Methodsmentioning

confidence: 99%

microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

et al. 2014

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“…Tumors having a score of <100 were classified as E-cadherin low and those with a score ≥100 as E-cadherin high (Figure 1). This dichotomous cut-point was determined prior to genetic association analyses and was based on the observed distribution of the composite scores and supported by evidence in the literature (11, 12). …”

Section: Methodsmentioning

confidence: 99%

Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression

Horne

Sherman

Pharoah

et al. 2013

Breast Cancer Res Treat

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E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions (EMT). In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95% CI 1.08 – 1.56) than with E-cadherin high tumors (OR = 1.06, 95% CI 0.95 – 1.18; case-only p-heterogeneity (p-het) = 0.05). Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations.

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“…ALDH1+ phenotype was found to be associated with biological aggressiveness and poor outcomes of breast cancer 9, 16, 17. Notably, several reports indicated that CD44 + /CD24 - and ALDH1+ breast cancer cells were associated with TNBC subtype 18-21. CD133, a transmembrane glycoprotein, is a more recent BCSC marker identified to be correlated with prognosis in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors

Yang¹,

Cao²,

Sun³

et al. 2016

Int. J. Biol. Sci.

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Triple-negative breast cancer (TNBC) is a tumor subtype with aggressive behavior and poor clinical outcome for lacking effective therapies. Breast cancer stem cells (BCSCs) have been suggested to have tumor-initiating properties, but it remains unclear whether their presence contributes to the increased aggressiveness and poor prognosis of TNBC. Also, the breast cancers display frequent inter- and intra-tumor heterogeneity, which adds the complexity in diagnosis and predicting prognosis. Here we investigated the clinical relevance and prognostic value of the BCSC markers, CD44+/CD24-, aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and CD133 in 88 TNBC cases. We found that a few patients displayed spatial heterogeneity of the BCSC markers in expression, which was defined as intratumor stemness heterogeneity (ITSH) below. There was no significant correlation between any BCSC marker alone or ITSH and progression-free survival (PFS). Interestingly, the combined BCSC phenotype by CD44+/CD24- and ALDH1A1 was significantly associated with worse PFS (P = 0.009). Further stratification analysis revealed that this combined BCSC phenotype was an independent prognostic factor for PFS in some subgroups. In conclusion, we demonstrated the existence of ITSH in TNBC and found that the ITSH as well as a single BCSC marker was not significantly associated with survival, whereas combing the analysis of BCSC markers could improve prognostic value. Our findings may lead to an improvement of prognostic indicators in TNBC.

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Stem cell-related markers in primary breast cancers and associated metastatic lesions

Cited by 32 publications

References 20 publications

microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

microRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers

Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression

Evaluation of Breast Cancer Stem Cells and Intratumor Stemness Heterogeneity in Triple-negative Breast Cancer as Prognostic Factors

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