Takeo Sakurai

Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian carcinoma syndrome. The primary objective of the current study was to investigate the influence of BRCA1 expression on the prognoses of sporadic breast carcinomas.

p63 expression in normal, hyperplastic and malignant breast tissues.

Backgroundp63 is a homologue of the p53 tumor suppressor gene and its protein is selectively expressed in the basal cells of a variety of epithelial tissues. It has recently been confirmed that p63 is expressed in the basal cells of normal prostate glands but not in prostatic carcinomas. Whether expression of p63 in breast correlates with tumor progression is the focus of this study.MethodsForty cases, which all contained normal breast tissue, ductal hyperplasia, ductal carcinomain situ and invasive ductal carcinoma in the same patient were included in this investigation using an indirect immunohistochemical method and double staining.Resultsp63 was exclusively expressed in the myoepithelial cells of normal breast, partially expressed in ductal hyperplasia, rarely expressed in carcinomain situ and not expressed in invasive carcinomas.ConclusionsThe results suggest an association between loss of p63 expression and progression of breast ductal carcinoma. p63 immunostaining might be of assistance for distinguishing invasive ductal carcinoma from ductal carcinomain situ or rare questionable ductal hyperplastic lesions, leading to correct therapy clinically.

Biallelic inactivation of retinoic acid receptor β2 gene by epigenetic change in breast cancer

A growing body of evidence supports the hypotheses that retinoic acid receptor beta2 (RAR beta2) is a tumor suppressor gene. Although the loss of RAR beta2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR beta2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR beta2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.

Evaluation of axillary lymph node status in breast cancer with MRI

BackgroundWe performed a retrospective study to establish the optimal radiological criteria for axillary lymph node metastases from breast cancer by measuring all dissected nodes, and to determine whether magnetic resonance imaging (MRI) could reliably reveal axillary involvement.MethodsPathological findings and MRI scans of 202 patients with invasive breast cancer were re-viewed. The long- and short-axis dimensions of all level I and II lymph nodes were measured micro-scopically, and then the long-to-short axis (L/S) ratio of each node was calculated. These parameters were compared with pathological nodal status to define radiological criteria for axillary involvement. MRI was carried out using T1-weighted spin-eho sequences in the coronal and sagittal planes. On MRI, every detected lymph node was measured and the shape of the nodal cortex was also examined. Then the diagnostic ability of MRI was assessed using these morphologic criteria.ResultsOn histopathological examinations of 4043 dissected lymph nodes, a long-axis dimension of 10 mm or larger combined with a long-to-short axis ratio of less than 1.6 was the most accurate criteria for predicting lymph node metastases. On MRI, eccentric cortical hypertrophy was seen in only metas-tatic axillae. When these morphologic features were used as criteria for malignancy, MRI had a sensi-tivity of 79%, a specificity of 93%, and an accuracy of 88%. In 16 of 17 false-negative axillae, MRI showed normally sized lymph nodes (<10 mm).ConclusionOur study indicates that MRI is a useful diagnostic method for the evaluation of axillary nodal status, but is limited in the detection of small metastatic lymph nodes.

Retinoid, Retinoic Acid Receptor β and Breast Cancer

Retinoids have been reported to inhibit the growth of several breast cancer cell lines in culture and to reduce breast tumor growth in animal models. Furthermore, retinoic acid (RA) can augment the action of other breast cancer cell growth inhibitors both in vitro and in vivo. Clinically, interest has increased in the potential use of retinoids for the prevention and treatment of human breast cancer. The regulation of cell growth and differentiation of normal, premalignant, and malignant cells by retinoids is mediated by the RA receptors (RARs) and retinoid X receptor. One of the target genes of retinoid receptors is RARβ2. A growing body of evidence supports the hypotheses that the RARβ2 gene is a tumor suppressor gene and the chemopreventive effects of retinoids are due to induction of RARβ2. RARβ2 expression is reduced in many malignant tumors including breast carcinoma. This paper will briefly discuss basic aspects of retinoids and retinoid acid receptor. In particular, we review what is now known for inactivation mechanism of RARβ2 and its role in tumor cell growth inhibition.

Chromosome 3p and breast cancer

AbstractSolid tumors in humans are now believed to develop through a multistep process that activates oncogenes and inactivates tumor suppressor genes. Loss of heterozygosity at chromosomes 3p25, 3p22–24, 3p21.3, 3p21.2–21.3, 3p14.2, 3p14.3, and 3p12 has been reported in breast cancers. Retinoid acid receptor β2 (3p24), thyroid hormone receptor β1 (3p24.3), Ras association domain family 1A (3p21.3), and the fragile histidine triad gene (3p14.2) have been considered as tumor suppressor genes (TSGs) for breast cancers. Epigenetic change may play an important role for the inactivation of these TSGs. Screens for promoter hypermethylation may be able to identify other TSGs in chromosome 3p. Alternatively, use of an “epigenetic modifier” may enhance the response to another type of agent for breast cancer.

Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma

Bcl‐2 and Bax have been demonstrated to be associated with apoptosis in breast carcinoma, and the ratio between Bax and Bcl‐2 seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl‐2, Bax and the proliferative activity of breast carcinoma. The purpose of this study was to investigate the significance of apoptosis‐related genes bcl‐2 and Bax and their correlation with expression of p53, tumor proliferation defined by MIB‐1 expression and estrogen receptor status. Immunohistochemistry was performed to determine Bcl‐2, Bax, p53, estrogen receptor (ER) and MIB‐1 expression in paraffin‐embedded tissues of 177 invasive breast cancers. Expression of the anti‐apoptotic protein Bcl‐2 was not correlated with the pro‐apoptotic Bax. Bcl‐2 immunostaining displayed a negative correlation with increasing histologic grade, p53 and MIB‐1 (P< 0.0001, P< 0.05 and P< 0.0001, respectively) and a positive correlation with rising ER immunostaining (r = 0.305, P< 0.0001). Conversely, expression of the apoptosis‐promoting protein Bax did not correlate with increasing histologic grade, p53, MIB‐1 or ER status. Neither Bcl‐2 expression nor Bax expression correlated with age, menopausal status, tumor size, histologic type or axillary lymph node status. These results imply that Bcl‐2 is associated with good prognostic markers and the regulation of Bax is complex and does not necessarily correlate with mutant p53 status in breast cancers.

Metaplastic Carcinoma of the Breast: p53 Analysis Identified the Same Point Mutation in the Three Histologic Components

A rare case of metaplastic carcinoma of the breast with both squamous metaplasia and cartilaginous metaplasia was reported. Histologically, the neoplasm revealed complex features, which were consisting of invasive ductal carcinoma, squamous carcinomatous component and chondrosarcomatoid component. Gradual transition of each component was recognized microscopically. p53 mutation analysis disclosed the same point mutation in three histologically different components, but not in the normal epithelium. Based on the morphologic findings, immunohistochemical findings and the p53 mutation analysis, we concluded that these three components in the tumor originated from the same duct progenitor cells.

Expression of Bcl-2 but not Bax or p53 correlates with in vitro resistance to a series of anticancer drugs in breast carcinoma

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.

Prognostic value of thymidine phosphorylase expression in breast carcinoma.

Thymidine phosphorylase (TP), also known as platelet‐derived endothelial cell growth factor (PD‐ECGF), is an enzyme that catalyzes the reversible dephosphorylation of thymidine, deoxyuridine and their analogs. TP has also angiogenic properties, although the precise mechanism by which it promotes angiogenesis is not known. We examined TP expression using immunohistochemistry (654‐1 Mab) in 182 invasive breast carcinomas (67 N0 and 115 N1/2; median follow‐up 78 months [range, 3–177]; 51 patients treated with adjuvant systemic cyclophosphamide, methotrexate and 5‐fluorouracil [CMF] chemotherapy and 82 with tamoxifen). High TP expression was found in 142 cases (78%) and correlated with lower histologic grade and low p53 expression. No correlation was found between TP expression and vascular density. TP‐positive tumors had a significant increase in both disease‐free survival (DFS; p = 0.0025) and overall survival (OS; p = 0.0070) in the total cohort of patients and in the subgroups of node‐positive patients and patients treated with CMF adjuvant therapy; no significant difference in either DFS or OS was observed in patients without CMF treatment. Our findings suggest that TP has little effect on tumor angiogenesis of breast carcinoma, whereas it could represent an interesting marker that could predict response to CMF chemotherapy.