Goro Yoshimura

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.

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.

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.

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.

Pamidronate-induced remission of pain associated with hypertrophic pulmonary osteoarthropathy in chemoendocrine therapy-refractory inoperable metastatic breast carcinoma.

We describe an extremely rare case of a woman with pulmonary metastatic disease from breast cancer, who presented with features of hypertrophic pulmonary osteoarthropathy (HPOA). Pain associated with HPOA may be extremely disabling and resistant to treatment. Treatment with pamidronate, an inhibitor of osteoclastic bone resorption, given every 2 weeks by i.v. drip infusion, led to rapid disappearance of uncontrolled pain caused by HPOA.

Calcitonin receptor gene and breast cancer: quantitative analysis with laser capture microdissection

There is a growing body of evidence indicating that calcitonin (CT) and its receptor (CTR) is involved in cell growth, differentiation and tissue development. Using laser capture microdissection (LCM) and real-time reverse transcription polymerase chain reactions (RT-PCR), we have investigated CTR mRNA expression in 60 primary breast cancers, including 14 pairs of matched cancers and unaffected ductal epithelia from the same patients. Our results demonstrate that CTR mRNA was constantly expressed in normal ductal epithelium and in breast cancer. In the 14 cases where matched samples were available, a decrease in CTR mRNA expression was found in 9 breast cancers (64.3%), an increased CTR expression in 2 cases (14.3%) and no significant change in 3 cases (21.4%). In 60 cases of primary breast cancers, decreased CTR expression was found in 44 (73.3%), increased CTR expression was detected in 10 cases (16.7%) and no change was observed in 6 cases (10%). Decreased CTR expression was found more often in cases with lymph node metastasis (p = 0.0498) and lymphatic invasion (p = 0.0179). Also there was a decreased CTR expression in cases with an extensive intraductal component (p = 0.0543) and a high nuclear grade (p = 0.1934), although this was not statistically significant. Overall, we conclude that CTR mRNA was constantly expressed in unaffected ductal epithelium, whereas decreased CTR mRNA expression was frequently found in breast cancers, particularly in cases with lymph node metastasis and lymphatic invasion. These results suggest that CTR might be of great potential significance in breast cancer progression.

Correlation between nuclear grade and biological prognostic variables in invasive Breast Cancer

BackgroundGrading of carcinomas is an estimation of differentiation. Nuclear grading is the cytological evaluation of tumor nuclei in comparison with the nuclei of normal mammary epithelial cells. Because nuclear grading does not involve an assessment of the growth pattern of the tumor, it applies not only to invasive ductal carcinoma but also to other subtypes of breast carcinoma.MethodsA total of 215 primary breast carcinomas obtained from the Affiliated Kihoku Hospital of Wakayama Medical College were enrolled in our present study. Nuclear grade was evaluated according to the criteria of the National Surgical Adjuvant Study of Breast Cancer (NSAS-B) protocol. Immuno-histochemistry was also performed to determine Bcl-2, p53, c-erbB-2, estrogen receptor (ER) and MIB-1 expression in paraffin-embedded tissues for all cases.ResultsThirty-two (14.9%) of the patients were graded as 1,124 (57.7%) as 2, and 59 (27.4%) as 3. Nuclear grade displayed a negative correlation with Bcl-2 expression (r=0.308, p<0.0001), and a positive correlation with c-erbB-2 overexpression (r= 0.172, p=0.01 17) and tumor proliferative index labeling by MIB-1 (r=0.485, p<0.0001).ConclusionsThese results imply that nuclear grade is related to the characteristics of tumor biology, indicating that the morphology and biology of breast cancer are tightly linked. Our present results also suggest that adding the nuclear grade to the pathological diagnosis of invasive breast carcinoma may be clinically useful for predicting tumor behavior, for example aggressiveness, and for prognostication.