No abstract

No abstract

Reticulin fibrosis was found in 21 of 40 patients with acute lymphocytic leukemia when marrows were studied sequentially by Vim-Silverman needle biopsies. Reticulin fibrosis frequently occurred early in the development of the disease. Mild degrees were completely reversible with remission, severe degrees usually persisted, even through remissions. Fibrosis appeared to develop during relapse. Duration of the disease in itself had little influence on the degree of reticulin fibrosis, and collagen fibrosis seldom followed reticulin fibrosis even after many months’ duration. The prognosis of patients with reticulin fibrosis of their marrows was definitely poorer than for the group without increased reticulin. Reticulin fibrosis virtually always prevented successful marrow biopsies by the standard technic of needle aspiration. Bone necrosis occurred in 11 of 75 patients with acute lymphocytic leukemia, but in none of 53 patients with acute myelogenous leukemia studied by Vim-Silverman needle biopsies during life or at autopsy. Bone necrosis was the major cause of severe bone pain and it was always associated with reticulin fibrosis of the marrow. Bone infarcts were not associated with short survival in all cases, but in general the prognosis of patients with bone necrosis was even poorer than that of patients with reticulin fibrosis but without demonstrable infarction.

NOP16, also known as HSPC111, has been identified as a MYC and estrogen regulated gene in in vitro studies, hence coexpression levels were strongly correlated. Importantly, high expression of NOP16 was associated with poor clinical outcome in breast cancer patients. However, coexpression of NOP16, MYC and estrogen receptor (ESR1) varied widely in tumors and cell lines suggesting that transcriptional regulation differed according to pathological environments. The goal of this study was to determine the expression patterns of Nop16, Myc and Esr1 in murine mammary tumors with disparate histopathological and molecular features. We hypothesized that tumor environments with relatively high Myc levels would have different coexpression patterns than tumor environments with relatively low Myc levels. We measured levels of Myc and Nop16 mRNA and protein in tumors from WAP-c-myc mice that were of high grade and metastasized frequently. In contrast, Myc and Nop16 mRNA and proteins levels were significantly lower in the less aggressive tumors that developed in NRL-TGFα mice. Tumors from both mouse lines express ESR1 protein and we found that Esr1 mRNA levels correlated positively with Myc levels in both models. However, Myc and Nop16 transcript levels correlated positively only in tumors from NRL-TGFα mice. We identified prominent NOP16 protein in nuclei and less prominent staining in the cytoplasm of luminal cells of ducts and lobules from normal mammary glands as well as in hyperplasias and tumors obtained from NRL-TGFα mice. This staining pattern was reversed in tumors from WAP-c-Myc mice as nuclear staining was faint or absent and cytoplasmic staining more pronounced. In summary, the regulation of expression and localization of NOP16 varies in tumor environments with high versus low MYC levels and demonstrate the importance of stratifying clinical breast cancers based on MYC levels.

Identification of biomarkers that indicate an increased risk of breast cancer or that can be used as surrogates for evaluating treatment efficacy is paramount to successful disease prevention and intervention. An ideal biomarker would be identifiable before lesion development. To test the hypothesis that changes in cell turnover precede mammary carcinogenesis, we evaluated epithelial cell proliferation and apoptosis in mammary glands from transgenic mice engineered to develop mammary cancer due to expression in mammary epithelia of transforming growth factor ␣ (TGF-␣) or c-myc. In transgenic glands, before lesion development, epithelial cell turnover was enhanced overall compared with nontransgenic glands, indicating that aberrant cell turnover in normal epithelia may contribute to tumorigenesis. In addition, in tumor-containing glands, proliferation in normal epithelia was higher than in tumor-free transgenic glands, suggesting these cell populations influence one another. Finally, although c-myc glands displayed a uniformly high epithelial cell turnover regardless of age, cell turnover was reduced with aging in nontransgenic and TGF-␣ mice, indicating that some growth and death regulatory mechanisms remain intact in TGF-␣ epithelia. These observations support the evaluation of cell turnover as a biomarker of cancer risk and indicator of prevention/treatment efficacy in preclinical models and warrant validation in human breast cancer.