A large-scale clinicopathological and long-term follow-up study of solid papillary carcinoma of the breast.

Solid papillary carcinoma of the breast (SPC) is a rare tumor of the breast with the unique histology and frequent neuroendocrine differentiation. However, a real nature and diagnostic importance of the neuroendocrine differentiation have not been properly handled. And relationship between SPC and the other types of invasive breast carcinoma, especially neuroendocrine tumor of the breast (NETb), has not been fully explained. We conducted a clinicopathological study of SPC to tackle these problems.In the study, we included 127 cases of SPC with long-term follow-ups of up to 30 years. The incidence in the breast carcinoma was 2.0%. The patients with SPC had a significantly better prognosis and no patients died of the tumor. The 35 cases had only SPC in situ (SPC-IS), while the 92 cases had both SPC-IS and SPC with invasion (SPC-INV). Immunohistochemically, 123 of the 127 cases exhibited diffuse expression of one or more neuroendocrine markers. Fifty of the 92 cases had exclusively invasive SPC (iSPC) as the invasive component. Twenty-two cases of iSPC were combined with NETb and the 18 cases with MUC. Six of 8 cases with metastatic SPC-INV disclosed iSPC in the axillary lymph node.This study suggests that SPC is immunohistochemically compatible with NET of the systemic organs (NETs). And the unique morphology of SPC may represent a traditional histology of NETs. The study also indicates that SPC has close relationship between NETb and type B MUC. And SPC and NETb may represent a spectrum of the same disease.

Identification of angiogenin as the osteoclastic bone resorption-inhibitory factor in bovine milk.

We identified, for the first time, the factor responsible for inhibiting osteoclast-mediated bone resorption in the basic protein fraction of bovine milk (milk basic protein, MBP). The protein was purified by a combination of ion and gel column chromatography from MBP, based on its activity to prevent unfractionated rabbit bone cells from forming pits on dentine slices. It was found to have a molecular weight of 15 kDa on SDS-PAGE, and the sequence of the N-terminal 25 amino acid residues was identical to that of bovine angiogenin. The purified bovine angiogenin inhibited the pit-forming activity of both unfractionated bone cells and purified osteoclasts in a dose-dependent manner, and the inhibitory activity was markedly suppressed by treatment with anti-bovine angiogenin antibody. The inhibitory activity was confirmed in mice both in vitro and in vivo. Treatment of osteoclasts with bovine angiogenin resulted in an impairment of the formation F-actin ring and a reduction in the mRNA levels of TRAP and cathepsin K, both known to be essential for the bone resorption activity of osteoclasts. These results suggest that bovine angiogenin is the substance mainly responsible for the inhibitory effect of bovine milk on osteoclast-mediated bone resorption, and that it exerts its activity by acting directly on the osteoclasts.

Solid-papillary carcinoma of the breast: clinicopathological study of 20 cases.

The purpose of the present paper was to evaluate the clinicopathological and biological features of 20 Japanese patients with solid-papillary carcinoma of the breast (SPC) or SPC associated with invasive breast cancer. All the patients were Japanese women, including two sisters. The mean age was 66.0 years. The incidence of SPC among all the breast cancers treated at two institutions was 1.1% and 1.7%, respectively. The mean disease-free interval was 4 years 11 months. Axillary lymph node metastasis or tumor recurrence did not occur in any of the cases. Fifteen cases of SPC contained invasive cancers that ranged from <5% to 60% of the entire tumor area. Histological types of invasive cancers were mucinous carcinoma in five cases and neuroendocrine cell carcinoma in 10 cases. These results indicate that SPC is a potential precursor lesion for neuroendocrine carcinoma as well as mucinous carcinoma. When all the cases were classified and analyzed according to both the 2002 tumor node metastasis (TNM) classification system and the Nottingham histological grade, SPC patients, even those with invasive cancers, seemed to have longer disease-free survival compared to patients with the other invasive breast cancers of matching grade and stage. Clinicopathologically, SPC could be regarded as a separate type of ductal carcinoma in situ.

Cystatin C in milk basic protein (MBP) and its inhibitory effect on bone resorption in vitro.

A cystein protease inhibitor was identified in the basic fraction of bovine milk. We have reported in our previous study that the milk basic protein (MBP) fraction suppressed osteoclast-mediated bone resorption in vitro. Since osteoclasts secreted cystein protease to digest collagen in the bone matrix, we identified the cystein protease inhibitor in MBP. A 12-kDa inhibitor was purified from MBP by papain affinity gel chromatography and subsequent Hi-Load Superdex 75 gel filtration chromatography. The N-terminal sequence of the 18 amino acid residues of the inhibitor corresponded to bovine cystatin C. The 12-kDa cystein protease inhibitor in MBP therefore seemed to be cystatin C. Purified cystatin suppressed bone resorption with the use of isolated osteoclasts in vitro. Cystatin in MBP is suggested as one of the factors inhibiting bone resorption.