Estrogen Receptor α–Negative Breast Cancer Tissues Express Significant Levels of Estrogen-Independent Transcription Factors, ERβ1 and ERβ5: Potential Molecular Targets for Chemoprevention

Poola, Indira; Fuqua, Suzanne A.W.; Witty, Robert L. De; Abraham, Jessy; Marshallack, Josephine J.; Liu, Aiyi

doi:10.1158/1078-0432.ccr-05-0728

Cited by 47 publications

(62 citation statements)

References 29 publications

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“…In our study, nuclear ERh1 expression was not significantly associated with good overall prognosis, nor did we observe any association with tamoxifen sensitivity. Studies of total breast mRNA have shown that ERh5 is the most abundantly expressed isoform in both ERa-positive and ERa-negative cases (32), but the potential contribution of nonepithelial ERh5 expression to these measurements is unknown: We have shown herein that ERh5 is additionally expressed in stromal and endothelial cells and immune infiltrates. The only other protein study on ERh5 in breast cancer was observational and conducted on just 17 cases (33).…”

Section: Discussionmentioning

confidence: 81%

Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

Shaaban

Green²,

Karthik

et al. 2008

Clinical Cancer Research

191

126

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Purpose: Previous conflicting results about the prognostic significance of estrogen receptor (ER)-h in breast cancer may be explained by contribution of isoforms, of which five exist. Our aim was to elucidate the prognostic significance of ERh1, ERh2, and ERh5 by immunohistochemistry in a large cohort of breast carcinomas with long-term follow-up. Experimental Design: Tissue microarrays were stained with ERh1, ERh2, and ERh5 antibodies and scored as percentage of positive tumor cells and using the Allred system. Nuclear and cytoplasmic staining was evaluated and correlated with histopathologic characteristics, overall survival (OS), and disease-free survival (DFS). Results: Nuclear ERh2 and ERh5, but not ERh1, significantly correlated with OS (P = 0.006, P = 0.039, and P = 0.099, respectively), and ERh2 additionally with DFS (P = 0.013). ERh2 also predicted response to endocrine therapy (P = 0.036); correlated positively with ERa, progesterone receptor, androgen receptor, and BRCA1; and correlated inversely with metastasis and vascular invasion. Tumors coexpressing ERh2 and ERa had better OS and DFS. Cytoplasmic ERh2 expression, alone or combined with nuclear staining, predicted significantly worse OS. Notably, patients with only cytoplasmic ERh2 expression had significantly worse outcome (P = 0.0014). Conclusions: This is the first study elucidating the prognostic role of ERh1, ERh2, and ERh5 in a large breast cancer series. ERh2 is a powerful prognostic indicator in breast cancer, but nuclear and cytoplasmic expression differentially affect outcome. Measuring these in clinical breast cancer could provide a more comprehensive picture of patient outcome, complementing ERa.

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Section: Discussionmentioning

confidence: 81%

Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

Shaaban

Green²,

Karthik

et al. 2008

Clinical Cancer Research

191

126

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“…As this was not found when ERb2/cx expression was assessed, it is likely that the correlation with total ERb reflects the ERb1 component, although we cannot exclude the existence of other, as yet unknown variant isoforms. Indeed, the frequent expression of the ERb variant isoform, ERb5, in ERanegative breast tumours has recently been described (Poola et al, 2005), however, we did not have access to specific antibodies to investigate this variant isoform in our breast tumour cohort. Our data confirm and extend an observation made by Jensen et al (2001), where the highest expression of either Ki67 and Cyclin A was found in tumours that only expressed ERb, indicating that ERb may be related to proliferation in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Expression of oestrogen receptor-β in oestrogen receptor-α negative human breast tumours

et al. 2006

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To analyse the phenotype of breast tumours that express oestrogen receptor-b (ERb) alone tissue microarrays were used to investigate if ERb isoforms are associated with specific prognostic markers and gene expression phenotypes in ERa-negative tumours. ERa-negative tumours were positive for ERb1 in 58% of cases (n ¼ 122/210), total ERb in 60% (n ¼ 115/192) and ERb2/cx in 57% of cases (n ¼ 114/199). Oestrogen receptor-b1 and total ERb were significantly correlated with Ki67 (r ¼ 0.28, Po0.0001, n ¼ 209; r ¼ 0.29, Po0.0001, n ¼ 191) and with CK5/6, a marker of the basal phenotype (r ¼ 0.20, P ¼ 0.0106, n ¼ 170; r ¼ 0.18, P ¼ 0.0223, n ¼ 158). ERb2/cx was strongly associated with p-c-Jun and NF-kBp65 (r ¼ 0.53, Po0.0001, n ¼ 93; r ¼ 0.35, Po0.0001, n ¼ 176). This study shows that a range of ERb isoform expression occurs in ERa-negative breast tumours. While expression of ERb1, total and ERb2/cx are correlated, individual forms show associations with certain phenotypes that suggest different roles in subsets of ERanegative cancers. Based on our in vivo observations, ERb may have the potential to become a therapeutic target in the specific subcohort of ERa-negative breast cancers.

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“…Immunohistochemistry was done randomly blinded to the knowledge on development/nondevelopment of cancer using standard procedures with a single batch of antibody preparation within 1 week on all of the samples. Briefly, slides were deparaffinized and antigens were retrieved in target retrieval solution (Dako) by heating for 25 min in a steamer as previously described (15,43,44) and blocked with 3% H 2 O 2 in methanol for 20 min. The slides were washed with PBS and incubated with avidin block (Vector Laboratories) for 10 min at room temperature followed by washing with PBS and incubating in biotin block (Vector Laboratories) for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias

Poola

Abraham

Marshalleck³

et al. 2008

Clinical Cancer Research

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Purpose: It has been reported that approximately a million women are diagnosed with benign breast lesions that include ductal hyperplasias per year in the United States. Recent studies that followed women with benign lesions have established that about 8% to 9% of them will subsequently develop invasive breast cancer (IBC). However, currently, there are no means of identifying a subclass of ''true precancerous tissues'' in women with ductal hyperplasias who will subsequently develop cancer. The purpose of this study is to investigate whether expression of hyaluronoglucosaminidase 1 (HYAL1), a known tumor promoter, in hyperplastic tissues identifies a ''true precancerous stage''and predicts subsequent IBC development. Experimental Design: A retrospective study was conducted with archival benign tissues of various histologic types and clinical information on development/nondevelopment of IBC. The control group was hyperplastic tissues from women who had no prior history of IBC and did not develop cancer in 5 to 7 years after diagnosis (n = 81). The test group was hyperplastic tissues from patients who developed cancer (n = 82). HYAL1 expression was studied by immunohistochemistry, and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value. Results: Statistical analysis of HYAL1expression data showed very highly significant association between its expression and subsequent cancer development (P = 0) and very high sensitivity (0.83), specificity (0.84), positive predictive value (0.84), and negative predictive value (0.83). Conclusions:The expression of HYAL1in ductal hyperplastic tissues is a strong predictor of subsequent development of IBC; therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to screen benign tissues to predict subsequent development of IBC. Detection at the precancerous stage and treatment could drastically cut down breast cancer incidence and deaths from it.

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Estrogen Receptor α–Negative Breast Cancer Tissues Express Significant Levels of Estrogen-Independent Transcription Factors, ERβ1 and ERβ5: Potential Molecular Targets for Chemoprevention

Cited by 47 publications

References 29 publications

Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients

Expression of oestrogen receptor-β in oestrogen receptor-α negative human breast tumours

Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias

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