ADAM28 is overexpressed in human breast carcinomas: implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3.

A disintegrin and metalloproteinases (ADAMs) are involved in various biological events including cell adhesion, cell fusion, membrane protein shedding, and proteolysis. In the present study, our reverse transcription-PCR analysis showed that among the 12 different ADAM species with a putative metalloproteinase motif, prototype membrane-anchored ADAM28m and secreted-type ADAM28s are selectively expressed in human breast carcinoma tissues. By real-time quantitative PCR, their expression levels were significantly higher in carcinomas than in nonneoplastic breast tissues. In situ hybridization, immunohistochemistry, and immunoblotting analyses indicated that ADAM28 is predominantly expressed in an active form by carcinoma cells within carcinoma tissues. A direct correlation was observed between mRNA expression levels and proliferative activity of the carcinoma cells. Treatment of ADAM28-expressing breast carcinoma cells (MDA-MB231) with insulin-like growth factor-I (IGF-I) increased cell proliferation, cleavage of IGF binding protein (IGFBP)-3, as well as IGF-I cell signaling; these processes were all significantly inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. Down-regulation of ADAM28 expression in MDA-MB231 cells with small interfering RNA significantly reduced cell proliferation, IGFBP-3 cleavage, and growth of xenografts in mice. In addition, cleavage of IGFBP-3 in breast carcinoma tissues was correlated with ADAM28 expression levels and inhibited by treatment with ADAM inhibitor or anti-ADAM28 antibody. These results show that ADAM28 is overexpressed in an activated form in human breast carcinoma cells and suggest that ADAM28 is involved in cell proliferation through enhanced bioavailability of IGF-I released from the IGF-I/IGFBP-3 complex by selective IGFBP-3 cleavage in human breast carcinomas.

Overview: current status of breast conserving therapy in Japan.

Breast conserving operations have become the standard operation for early breast cancer. They were performed in about 40% of all breast cancer patients in Japan in 2000, and the percentage is still increasing. Ductal carcinoma in situ (DCIS) accounts for about 7% of all breast cancers and breast conserving operations for DCIS have been followed by a low in-breast recurrence rate, leading to wider indications for breast conserving operations as screening mammography has come to be used in Japan. In-breast recurrence is correlated to surgical margin status. It is important to evaluate the surgical margin for volume of cancer cell nests as well as for positivity. Neoadjuvant chemotherapy has become popular as an in vivo sensitivity test and as a means of down-staging to increase the possibility of performing a breast conserving operation. There are two patterns of shrinkage when neoadjuvant chemotherapy is effective: cocentric and honeycomb, and the pattern of residual cancer cell nests must be determined before surgery. MRI is an effective method of evaluating residual cancer cell nests. The in-breast recurrence rate after down-staging to perform breast conserving operations is reported to be higher than among candidates for breast conserving operation at the start. Sentinel node biopsy techniques and endoscopic operations are now being assessed in conjunction with breast conserving operations. The current status of breast conserving operations in Japan is reviewed in comparison with their status in Western countries.

[Breast cancer].

Adjuvant chemo-endocrine therapy for breast cancer (ACETBC) trial has been the first large scaled clinical trial performed in Japan. Several prospective randomized trials have been performed in Japan since ACETBC-1 trial started in 1985. The effect of oral 5-FU agents had been tested in prospective randomized trials and the statistically marginal effect of oral 5-FU agents in adjuvant settings has been reported. Several trials having CMF as a control arm started in 1996 when CMF combination chemotherapy was approved by the government. The results of these trials have not been published. To perform good clinical trials, it is imperative to construct infrastructures including clinical research coordinator, and abolish governmental regulation of the dose of anticancer agents.

[Developments in endocrine therapy for breast cancer].

After the usefulness of ovariectomy in breast cancer patients was demonstrated, endocrine therapy has been one of the most effective treatments of breast cancer. Thereafter, it became clear that estrogen receptors (ERs) existed in the cells of breast cancer. After it was found that ERs could be used as a predictive factor of endocrine therapy for breast cancer, the validity of endocrine therapy has became more certain. Tamoxifen, a major selective estrogen receptor modulator, is the first agent which has shown evidence of improving survival time and disease-free survival time in the treatment of breast cancer, and is the standard treatment, widely used in the treatment of breast cancer all over the world. LH-RH analogue, commonly used in ablation treatment among premenopausal women, produces the same effect as ovariectomy, and recently has shown good results equivalent to chemotherapy in premenopausal breast cancer treatment. Furthermore, aromatase inhibitors as a form of ablation treatment of postmenopausal women have been used recently. In comparison with tamoxifen, aromatase inhibitors have revealed the same or more effective result in postmenopausal breast cancer treatment. In the near future, endocrine mechanisms in the body and the molecular mechanisms of transcription by ER will be more clearly elucidated, and then new kinds of agent and combined therapies for the endocrine treatment of breast cancer will be developed. Currently, many clinical randomized trials are being conducted to examine the effectiveness of new endocrine treatment. Significant changes are occurring in the endocrine treatment of breast cancer.

[Predictive factors affect the choice of strategy for breast cancer surgery].

Predictive factors are those factors that predict the effects of chemotherapeutic or other agents on the tumor or the host. Many factors have been investigated for their predictive value of the effect of chemotherapeutic or hormonal agents. Estrogen or progesterone receptors are the most established predictive factors for hormonal therapy. Her-2/neu is a predictive of the effect of the monoclonal antibody trastuzumab and of certain chemotherapeutic agents. Other predictive factors remain under clinical investigation. Most cases of breast cancer are initially considered to be systemic disease. Cure can only achieved with surgery that leaves no residual cancer cells, followed by an appropriate form of systemic therapy. In the clinical situation, local therapy and systemic therapy for breast cancer have been considered independently. However, preoperative chemotherapy has become common recently. The interaction between chemotherapy and surgery should be considered because the results of preoperative chemotherapy affect the choice of operative technique. Predictive factors for the effect of radiation therapy should also be taken into account after breast-conserving surgery. It remains to be determined which predictive factors should be considered at which time.

Dose-related fluorodeoxyglucose uptake in acute radiation-induced hepatitis.

Therapeutic assessment with fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is sometimes problematic after radiation therapy. Herein we describe a patient with acute radiation-induced hepatitis in which PET showed dose-dependent FDG uptake. A 50-year-old man underwent FDG PET for staging of esophageal cancer. Chemoradiotherapy was delivered concurrently with a radiation field that expanded from the esophagus into the upper stomach to cover metastasis of the gastric wall. The patient also underwent FDG PET 26 days and 4 months after chemoradiotherapy to evaluate the therapeutic effect. Twenty-eight days after chemoradiotherapy, hematochemistry revealed elevated hepatic enzymes and postcontrast computed tomography showed band-like hypoattenuation in the liver with parenchymal swelling corresponding to the radiation field. FDG PET performed 26 days after chemoradiotherapy showed a wedge-shaped hypermetabolic area in which the degree of FDG uptake correlated with the prescribed radiation dose. Follow-up PET 4 months after therapy showed no abnormal uptake in the liver. Acute radiation-induced hepatitis can be a potential cause of false-positive findings of malignancy on FDG PET scans, and PET images should carefully be compared with the distribution of prescribed dose. Threshold dose might be higher for metabolic changes than for morphologic changes.