Jay N. Umbreit

Inhibition of Breast Cancer Metastasis by Selective Synthetic Polypeptide against CXCR4

Metastasis shares many similarities with leukocyte trafficking. Among those chemokine receptors thought to be involved in hemopoietic cell homing, stromal cell-derived factor-1 and its receptor CXC chemokine receptor-4 (CXCR4) have received considerable attention. Like hemopoietic cell homing, levels of stromal cell-derived factor-1 are high at sites of breast cancer metastasis including lymph node, lung, liver, and the marrow. Moreover, CXCR4 expression is low in normal breast tissues and high in malignant tumors, suggesting that a blockade of CXCR4 might limit tumor metastasis. We therefore investigated the role of a synthetic antagonist 14-mer peptide (TN14003) in inhibiting metastasis in an animal model. Not only was TN14003 effective in limiting metastasis of breast cancer by inhibiting migration, but it may also prove useful as a diagnostic tool to identify CXCR4 receptor-positive tumor cells in culture and tumors in paraffin-embedded clinical samples.

Dibenzoylmethane, a natural dietary compound, induces HIF-1α and increases expression of VEGF

Abstract Hypoxia-inducible factor 1 (HIF-1) is the major transcription factor activated during hypoxia. It is composed of HIF-1α and HIF-1β subunits. While HIF-1β is constitutively expressed, HIF-1α is targeted to proteasome degradation under normoxic conditions. Under hypoxia, HIF-1α is stabilized and heterodimerizes with HIF-1β. Iron chelators have also been reported to stabilize HIF-1α protein and activate HIF-1. In this study, we investigated the effects of dibenzoylmethane (DBM), a natural dietary compound and an iron chelator, on HIF-1 pathway. We found that DBM increases HIF-1α protein levels in a dose- and time-dependent manner. This induction was accompanied with activation of HIF-1, measured by reporter gene assay and increased production of its downstream target, the vascular endothelial growth factor. Mechanistically, HIF-1α was stabilized by DBM at a step prior to ubiquitination. The effect of DBM on HIF-1 and its low toxicity profile might be therapeutically beneficial in ischemic diseases.

Expression of e-cadherin in high-risk breast cancer

Purpose E-cadherin expression is diverse, and differences in patient characteristics may produce variability in expression. Whereas some studies have indicated that downregulation of e-cadherin, associated with loss of cellular adhesiveness, was correlative with poor prognosis and metastasis, other studies have failed to confirm this. The present study uses a highly homogenous population of patients at high-risk for breast cancer, on the basis of ethnic and socio-economic status, to examine the relationship between e-cadherin and other prognostic markers in breast cancer.Methods Immunohistochemical staining was undertaken for estrogen (ER) and progesterone (PR) receptors, epidermal growth factor receptor 2 (Her-2), p53, vascular endothelial factor (VEGF), and hypoxia inducible factor 1α (HIF-1α) and the levels of these markers was compared to e-cadherin expression in a high-risk African-American patient population.Results E-cadherin expression persisted into the later stagers of the disease, and was strongly associated with Her-2 and HIF-1α expression, but not p53, ER/PR or VEGF.Conclusions In contrast to other studies on heterogeneous populations, e-cadherin is preserved in aggressive tumors in this high-risk population. The ethnic and socio-economic risk stratification needs to be accounted for in studies correlating markers and prognosis.

Correlation and expression of p53, HER-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast-cancer population.

BackgroundMany genetic traits common to aggressive breast carcinoma have been identified; yet little is known about the interrelationships of such traits during tumor development, especially in women prone to aggressive cancer. This study examined the expression of four biological markers associated with poor prognosis at each stage of breast cancer progression in primary tumors from women of lower economic status and assessed the relationship between these markers.MethodsArchived primary breast tumors from 77 patients were assessed by immunohistochemical analysis for expression of human epidermal growth receptor 2 (HER-2), p53, vascular endothelial growth factor (VEGF), and e-cadherin, and the relationships between the expressions of these molecules were studied.ResultsTwenty-two (29%) patients had advanced (stage III or IV) disease. HER-2, VEGF, e-cadherin, and p53 signal were positive for 31 (40%), 58 (75%), 63 (82%), and 37 (48%) of patients, respectively. Among the markers tested, only p53 exhibited a significant association between expression and stage of the disease (P = 0.012). Expression of e-cadherin was positively associated with HER-2 overexpression (P = 0.004), and high levels of HER-2 occurred with strongly positive e-cadherin tumors. Marginally significant positive associations were observed between HER-2 and p53 signal (P = 0.06), and between disease stage and e-cadherin expression (P = 0.08).ConclusionThe significant tendency toward expression of e-cadherin in conjunction with HER-2 overexpression in breast cancer is a novel finding. The association of p53 with more advanced stages of cancer emphasizes it as a key participant in metastatic processes in breast cancer.

Fatal exacerbation of paraneoplastic systemic sclerosis after neoadjuvant chemotherapy in a breast cancer patient

Paraneoplastic systemic sclerosis (SSc) occurs in about 3%–7% of individuals with SSc. There are reports of accelerated SSc syndromes associated in particular with breast cancer. Further exacerbations of the rheumatic condition may be induced by treatment of the cancer. We report a 30-year-old African-American woman with a contiguous diagnosis of breast cancer and paraneoplastic SSc. She was treated with neoadjuvant chemotherapy and developed an accelerated SSc syndrome with pericarditis and cardiac tamponade, with lethal results. This case report stresses the need for control of the rheumatic condition prior to the initiation of antineoplastic therapy.