Expression levels of estrogen receptor (ER) A govern estrogendependent growth, response to endocrine therapy, and prognosis in ERA-positive breast cancer. Multiple mechanisms involved in altering ERA gene expression in breast cancer have been identified, including ERA gene amplification as well as transcriptional silencing by DNA methylation of CpG islands within the ERA promoter and mutations within the open reading frame of ERA. However, expression levels of ERA in breast cancer tissues differ widely among patients, and frequently change during disease progression and in response to systemic therapies. Recent evidence has shown that microRNA mutations or misexpression correlate with various human cancers, and miR-206 is reported to decrease endogenous ERA mRNA and protein levels in human MCF-7 breast cancer cells via two specific target sites within the 3 ¶-untranslated region of the human ERA transcript. In this study, we show for the first time that miR-206 expression is markedly decreased in ERA-positive human breast cancer tissues assayed by quantitative reverse transcription-PCR analysis. Moreover, we observe that miR-206 expression is inversely correlated with ERA but not ERB mRNA expression in breast cancer tissues. Transfection experiments revealed that introduction of miR-206 into estrogen-dependent MCF-7 breast cancer cells inhibits cell growth in a dose-and timedependent manner. Our results suggest that miR-206 could be a novel candidate for endocrine therapy that targets only ERA in breast cancer. [Cancer Res 2008;68(13):5004-8]

Purpose:The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients.Experimental Design: In the present study, the level of HDAC6 mRNA expression was analyzed with quantitative real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also determined by immunohistochemistry. An association was sought between HDAC6 expression and various clinicopathologic factors.Results: HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histologic grade, and in estrogen receptor ␣-and progesterone receptor-positive tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate analysis failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathologic factors.Conclusions: We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Additional investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.

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Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer via its binding to the estrogen receptor alpha (ERalpha). Recent data indicate that chromatin inactivation mediated by histone deacetylation (HDAC) and DNA methylation is a critical component of ERalpha silencing in human breast cancer cells. The aim of this study was to determine the expression of the HDAC1 gene in malignant human breast tissue and to correlate our observations with available clinical information. In the present study, the level of expression of HDAC1 mRNA was assessed by LightCycler-based quantitative real-time reverse transcriptase (RT)-PCR analysis in 162 cases of invasive carcinoma of the breast. Associations between HDAC1 mRNA expression and different clinicopathological factors were sought. It was found that HDAC1 mRNA was expressed at significantly higher levels in tumors from patients over 50 years of age and in those tumors without axillary lymph node involvement, that are less than 2 cm, that are of a non-high histological grade, that are HER2 negative and that are ERalpha/PgR positive. Patients with tumors displaying high levels of HDAC1 mRNA expression tended to have a better prognosis in terms of both disease-free and overall survival. However, univariate and multivariate analysis did not show HDAC1 mRNA expression level to be an independent prognostic factor for either disease-free or overall survival. These results imply that HDAC1 mRNA expression could have potential as an endocrine response marker and may have prognostic implications for breast cancer progression.

The role of estrogen receptor (ER) α as a target in treatment of breast cancer is clear, but those of ERβ1 and ERβ2 in the breast remain unclear. We have examined expression of all three receptors in surgically excised breast samples from two archives: (i): 187 invasive ductal breast cancer from a Japanese study; and (ii) 20 lobular and 24 ductal cancers from the Imperial College. Samples contained normal areas, areas of hyperplasia, and in situ and invasive cancer. In the normal areas, ERα was expressed in not more than 10% of epithelium, whereas approximately 80% of epithelial cells expressed ERβ. We found that whereas ductal cancer is a highly proliferative, ERα-positive, ERβ-negative disease, lobular cancer expresses both ERα and ERβ but with very few Ki67-positive cells. ERβ2 was expressed in 32% of the ductal cancers, of which 83% were postmenopausal. In all ERβ2-positive cancers the interductal space was filled with dense collagen, and cell nuclei expressed hypoxia-inducible factor 1α. ERβ2 expression was not confined to malignant cells but was strong in stromal, immune, and endothelial cells. In most of the high-grade invasive ductal cancers neither ERα nor ERβ was expressed, but in the high-grade lobular cancer ERβ was lost and ERα and Ki67 expression were abundant. The data show a clear difference in ER expression between lobular and ductal breast cancer and suggest (i) that tamoxifen may be more effective in late than in early lobular cancer and (ii) a potential role for ERβ agonists in preventing in situ ductal cancers from becoming invasive.ductal carcinoma in situ | invasive ductal carcinoma | invasive lobular carcinoma

Objective: A needs assessment can be used as a direct index of what patients perceive they need help with. The purposes of this study were to investigate the association between patients' perceived needs and psychological distress and/or quality of life (QOL) and to clarify the characteristics of patients with a high degree of unmet needs.Methods: Randomly selected ambulatory female patients with breast cancer participated in this study. The patients were asked to complete the Short-form Supportive Care Needs Survey questionnaire, which covers five domains of need (health system and information, psychological, physical, care and support, and sexuality needs); the Hospital Anxiety and Depression Scale; and the European Organization for Research and Treatment of Cancer QLQ-C 30.Results: Complete data were available for 408 patients. The patients' needs were significantly associated with both psychological distress (r 5 0.63, po0.001) and QOL (r 5 À0.52, po0.001). A multiple regression analysis revealed that employment status (without full-time /part-time job), duration since diagnosis (less than 6 months), advanced stage, and a lower performance status were significantly associated with higher total needs. Only sexuality needs were significantly associated with a younger age, while the other domains were significantly associated with duration since diagnosis, advanced stage, and a lower performance status.Conclusions: Moderate to strong associations exist between patients' needs and psychological distress and/or QOL. The characteristics associated with patients' needs are multi-factorial, and interventions to respond to patients' needs may be one possible strategy for ameliorating psychological distress and enhancing QOL.

Purpose Patient-reported outcomes (PROs) are used increasingly for individual patient management. Identifying which PRO scores require a clinician’s attention is an ongoing challenge. Previous research used a needs assessment to identify EORTC-QLQ-C30 cut-off scores representing unmet needs. This analysis attempted to replicate the previous findings in a new and larger sample. Methods This analysis used data from 408 Japanese ambulatory breast cancer patients who completed the QLQ-C30 and Supportive Care Needs Survey-Short Form-34 (SCNS-SF34). Applying the methods used previously, SCNS-SF34 item/domain scores were dichotomized as no vs. some unmet need. We calculated area under the receiver operating characteristic curve (AUC) to evaluate QLQ-C30 scores’ ability to discriminate between patients with no vs. some unmet need based on SCNS-SF34 items/domains. For QLQ-C30 domains with AUC≥0.70, we calculated the sensitivity, specificity, and predictive value of various cut-offs for identifying unmet needs. We hypothesized that compared to our original analysis (1) the same six QLQ-C30 domains would have AUC≥0.70, (2) the same SCNS-SF34 items would be best discriminated by QLQ-C30 scores, and (3) the sensitivity and specificity of our original cut-off scores would be supported. Results The findings from our original analysis were supported. The same six domains with AUC≥0.70 in the original analysis had AUC≥0.70 in this new sample, and the same SCNS-SF34 item was the best discriminated by QLQ-C30 scores. Cut-off scores were identified with sensitivity≥0.84 and specificity≥0.54. Conclusion Given these findings’ concordance with our previous analysis, these QLQ-C30 cut-offs could be implemented in clinical practice and their usefulness evaluated.

Prognostic biomarkers in a disease provide information regarding outcome irrespective of therapy. Candidate prognostic biomarkers in breast cancer include elevated levels of expression of proliferation indices such as Ki67 and proliferating cell nuclear antigen; expression of estrogen receptor (ER) and progesterone receptor; amplification and over-expression of HER2, cyclin D 1 , and c-myc; p53 nuclear protein accumulation; bcl-2 expression; and alteration in angiogenesis proteins such as vascular endothelial growth factor [1][2][3][4][5]. In particular, review of the literature suggests that over-expression of HER2 and p53 may have prognostic significance in breast cancer. HER2 (c-erbB2) encodes a membrane protein (p185) that is tyrosine phosphorylated after interaction with its ligands. Over-expression of HER2 occurs through either amplification of the gene or mRNA over-expression. p53 is involved in regulating cell proliferation, inducing apoptosis, and in promoting chromosomal stability. Disruption of these functions appears to play an important role in carcinogenesis. There is evidence that over-expression of HER2 and p53 is involved in breast cancer progression [6]. This hypothe-CMF = cyclophosphamide, methotrexate, and fluorouracil; ER = estrogen receptor. Breast Cancer ResearchVol 6 No 1 Yamashita et al. Research article Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancerHiroko Yamashita 1 , Mariko Nishio 1 , Tatsuya Toyama 1 , Hiroshi Sugiura 1 , Zhenhuan Zhang 1 , Shunzo Kobayashi 2 and Hirotaka Iwase 1 1 Breast and Endocrine Surgery, Nagoya City University Hospital, Nagoya, Japan 2 Josai Municipal Hospital of Nagoya, Nagoya, Japan et al., licensee BioMed Central Ltd (Print ISSN 1465-5411; Online ISSN 1465-542X). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. AbstractIntroduction: Many laboratories are currently evaluating the usefulness of determination of HER2, p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in cancer patients, their clinical usefulness is still controversial.