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.

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.

Endocrine therapy has become the most important treatment option for women with estrogen receptor (ER)-positive breast cancer. Urgently needed are prognostic assays that can identify those who need additional adjuvant therapy, such as signal transduction inhibitors or chemotherapy, for ER-positive early breast cancer. We examined phosphorylation of ERa serine (Ser) 118, ERa Ser167, p44/42 mitogen-activated protein kinase (MAPK), and Akt and expression of progesterone receptor, amplified in breast cancer 1 (AIB1), human epidermal growth factor receptor 2 (HER2), p53, and Ki67 in ER-positive breast cancers by immunohistochemistry, and analyzed their significance for prognosis. Phosphorylation levels of ERa Ser118, ERa Ser167, MAPK, and Akt were positively correlated. AIB1 expression was significantly associated with phosphorylation of ERa Ser118, MAPK, and Akt, and HER2 expression. Low phosphorylation of ERa Ser118 and high phosphorylation of ERa Ser167 were associated with significantly improved disease-free (PZ0.0003 and PZ0.0002 respectively) and overall survival (PZ0.0007 and PZ0.0016 respectively) in multivariate analyses. Our data suggest that phosphorylation of ERa Ser118 and ERa Ser167 affects survival in ER-positive breast cancer and could be helpful in distinguishing patients who are likely to benefit from endocrine therapy alone from those who are not.

Introduction Endocrine therapy is the most important treatment option for women with hormone-receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and crosstalk between ER and other growth factor signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified.

Down regulation of the ING1 candidate tumour suppressor promotes growth in soft agar and focus formation in vitro and tumour formation in vivo. ING1 encodes a nuclear, cell cycle-regulated protein, overexpression of which e ciently blocks cell growth and is capable of inducing apoptosis in di erent experimental systems. Here we present the ®rst report of ING1 mutation and expression analysis in a total of 452 cancer samples. One germline missense alteration and three germline silent alterations were detected in 377 primary breast cancers while marked (2 ± 10-fold) decreases in ING1 mRNA expression were seen in 44% of primary breast cancers and in ten of ten breast cancer cell lines examined. Furthermore, the majority of breast cancers (58%) showing decreased ING1 expression had metastasized to regional lymph nodes whereas only 9% of cancers with elevated ING1 expression, compared to adjacent normal tissues, were metastatic. Thus, ING1 mutation is very rare in breast or ovarian cancers, however, repression of ING1 expression frequently accompanies tumour development of breast cancer.