Faculty Publications

Human enhancer of invasion, clone 10 (HEI10) (CCNB1IP1) was first described as a RING-finger family ubiquitin ligase that regulates cell cycle by interacting with cyclin B and promoting its degradation. Subsequently, other studies suggested specific upregulation of HEI10 in metastatic melanoma and demonstrated direct interaction between HEI10 and the tumor suppressor Merlin, encoded by the neurofibromatosis 2 gene. These and other results led us to hypothesize that HEI10 also influences the processes of cell migration and metastasis. We here show that cells with depleted HEI10 both migrate more rapidly and invade more effectively than control cells. HEI10 depletion post-transcriptionally increases the expression of a group of promotility regulatory proteins including p130Cas, paxillin, Cdk1 and cyclin B2, but excluding Merlin. Among these, only inhibition of Cdk1/cyclin B activity specifically reversed the motility and invasion of HEI10-depleted cells. Finally, HEI10 is abundantly transcribed in many human tissues, and particularly abundant in some tumor cell lines, suggesting that it may be commonly involved in coordinating cell cycle with cell migration and invasion.

The impact of immunotherapy on the natural progression of cutaneous T-cell lymphoma ( CTCL), particularly the mycosis fungoides and Sezary syndrome variants, has been based on our evolving understanding of the disease's immunobiology.

We previously identified a small number of genes using cDNA arrays that accurately diagnosed patients with Sezary Syndrome (SS), the erythrodermic and leukemic form of cutaneous T-cell lymphoma (CTCL). We now report the development of a quantitative real-time polymerase chain reaction (qRT-PCR) assay that uses expression values for just 5 of those genes: STAT4, GATA-3, PLS3, CD1D, and TRAIL. qRT-PCR data from peripheral blood mononuclear cells (PBMCs) accurately classified 88% of 17 patients with high blood tumor burden and 100% of 12 healthy controls in the training set using Fisher linear discriminant analysis (FLDA). The same 5 genes were then assayed on 56 new samples from 49 SS patients with blood tumor burdens of 5% to 99% and 69 samples from 65 new healthy controls. The average accuracy over 1000 resamplings was 90% using FLDA and 88% using support vector machine (SVM). We also tested the classifier on 14 samples from patients with CTCL with no detectable peripheral i! nvolvement and 3 patients with atopic dermatitis with severe erythroderma. The accuracy was 100% in identifying these samples as non-SS patients. These results are the first to demonstrate that gene expression profiling by quantitative PCR on a selected number of critical genes can be employed to molecularly diagnosis SS.

Background: Gene expression profiling of melanoma and nevic tissue has demonstrated that pleiotrophin (PTN) is significantly overexpressed in human melanomas. Methods: To further evaluate PTN expression in melanocytic lesions, protein immunohistochemistry was performed on the spectrum of melanocytic lesions. Results: Melanocytic nevi were consistently negative (n = 58). In contrast, the great majority of metastatic melanomas were positive (33/34, 97%). The analysis of 34 primary melanomas demonstrated PTN positivity in 20 lesions while 14 lesions were negative. Within the primary melanomas, PTN immunoreactivity was associated with metastasis (p = 0.0004) and decreased melanoma-related survival (p = 0.0444). Univariate analysis of PTN immunoreactivity predicted an increased risk for metastasis (relative risk 9.1, p = 0.003). Conclusions: The results of this study confirm previous gene profiling data showing differential PTN expression between melanocytic nevi and melanomas. In addition, lesional PTN expression is associated with metastatic potential and may be a prognostic factor for melanomas.

Objectives. To review the world literature for reports of cutaneous metastases from primary genitourinary malignancies and compare them with our experience during a 10-year period. Cutaneous metastases from primary visceral malignancies are uncommon manifestations of advanced disease. Among patients with urologic malignancies, the incidence and appearance of cutaneous metastases are not well established and recognition is poor among practicing urologists. Methods. A Medline search and manual bibliographic review was performed to identify peer-reviewed reports pertaining to cutaneous metastases from all visceral malignancies. A comparative review of all pertinent cases arising from primary urologic malignancies was performed. A comprehensive search of our institution's tumor registry was performed to identify all analytic cases of urologic malignancy diagnosed, treated, and followed up between 1990 and 2000. Clinical and pathologic data were collated. Results. We identified 2,369 reported cases of cutaneous metastases arising from 81,618 primary solid visceral malignancies, for an overall incidence of 2.9%. Dermatologic spread from primary urologic malignancies of the kidney, bladder, prostate, or testes was noted in 116 (1.3%) of 10,417. The incidence of cutaneous metastases from the kidney, bladder, prostate, and testes was 3.4%, 0.84%, 0.36%, and 0.4%, respectively. Overall, 436 cases of cutaneous metastases from urologic organs were identified in the English-language literature. We identified nine additional cases of pathologically confirmed cutaneous metastatic urologic tumors at our institution in the past 10 years. The most common presentation was an infiltrated plaque or nodules. Most cases displayed clinical features that mimicked common skin disorders. The median disease-specific survival was less than 6 months from the presentation of cutaneous metastasis. Conclusions. Cutaneous metastases from urologic tumors are uncommon and occur in 1% of patients with advanced disease. Urologic skin metastases are most common from renal tumors, followed by those of the bladder and then prostate. Their clinical appearance may mimic other common dermatologic disorders affecting patients with advanced malignancies. Definitive diagnosis requires an index of suspicion and skin biopsy. Cutaneous metastases from urologic malignancies are associated with a poor prognosis. (C) 2004 Elsevier Inc.

Background. Little is known about acceptance of skin cancer risk-reduction practices and attitudes among individuals with a family history of melanoma. The purpose of this study was to examine engagement in and correlates of sun protection, total cutaneous examination (TCE), and skin self-examination (SSE) among first-degree relatives (FDR) of individuals diagnosed with malignant melanoma (MM). Method. First degree relatives (N = 229) completed measures of engagement in TCE, SSE, and habitual sun protection, as well as measures of knowledge and attitudes about all three behaviors. Results. Slightly more than 50% of family members reported having TCE, and engagement in habitual sun protection was relatively low. Engagement in SSE was higher. Regression analyses revealed that physician recommendation and perceived barriers were consistent correlates of all three risk-reduction behaviors. Self-efficacy and normative influences were also associated with sun protection. Conclusions. Engagement in skin cancer risk-reduction practices among individuals with a family history of melanoma is relatively low. Interventions to improve acceptance would benefit from targeting both nonpsychological and psychological factors, particularly physician influence and perceived barriers. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved.