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- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 1987-1994
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERalpha)-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen.EXPERIMENTAL DESIGN: We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.RESULTS: ERbeta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERalpha-negative patients (P = 0.003; P = 0.04), but not in the ERalpha-positive subgroup (P = 0.49; P = 0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature.CONCLUSION: Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the United States alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen.
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| 2. |
- Honeth, Gabriella, et al.
(författare)
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The CD44(+)/CD24(-) phenotype is enriched in basal-like breast tumors
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Human breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44(+)/CD24(-) phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Methods Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data were also accessible for a cohort of the material. Results A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44(+)/CD24(-), CD44(-)/CD24(+) and CD44(+)/CD24(+) phenotypes. CD44(+)/CD24(-) cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44(+)/CD24(-) phenotype was most common in the basal-like subgroup-characterized as negative for the estrogen and progesterone receptors as well as for HER2, and as positive for cytokeratin 5/14 and/or epidermal growth factor receptor, and particularly common in BRCA1 hereditary tumors, of which 94% contained CD44(+)/CD24(-) cells. The CD44(+)/CD24(-) phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24(+) status. A CD44(+)/CD24(-) gene expression signature was generated, which included CD44 and alpha(6)-integrin (CD49f) among the top-ranked overexpressed genes. Conclusion We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and the presence of CD44(+)/CD24(-) cells. Not all basal-like tumors and very few HER2+ tumors, however, contain CD44(+)/CD24(-) cells, emphasizing that a putative tumorigenic ability may not be confined to cells of this phenotype and that other breast cancer stem cell markers remain to be identified.
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| 3. |
- Jumppanen, Mervi, et al.
(författare)
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Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers
- 2007
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor ( ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup. Methods IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset ( 100) of the breast tumors ( including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed. Results From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years ( 3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period ( 10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes ( p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification. Conclusion Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors.
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