Faculty Bibliography

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are higher in African-Americans as compared with other racial/ethnic groups. The women's health initiative (WHI) study sample was used to determine whether differences in CRC risk factors explain racial/ethnic differences in incidence and mortality. METHODS: The WHI is a longitudinal study of postmenopausal women recruited from 40 centers. Baseline questionnaires were used to collect sociodemographic and health status information. All CRC diagnoses were centrally adjudicated. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by race/ethnicity. RESULTS: The study sample included 131,481 (83.7%) White, 14,323 (9.1%) African-American, 6,362 (4.1%) Hispanic, 694 (0.4%) Native American and 4,148 (2.6%) Asian/Pacific Islanders. After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was the highest in African-Americans (annualized rate = 0.14%), followed by Whites and Native Americans (0.12% each), Asian/Pacific Islanders (0.10%), and Hispanics (0.08%). After adjustment for age and trial assignment, Hispanics had a lower risk compared with Whites, HR 0.73 (95% CI: 0.54-0.97) (P = 0.03), and African-Americans had a marginally greater risk, HR 1.16 (95% CI: 0.99-1.34), P = 0.06. Multivariable adjustment attenuated the difference in incidence between African-Americans and Whites (HR 0.99, 95% CI: 0.82-1.20), while strengthening the lower HR for Hispanics (HR 0.68, 95% CI: 0.48-0.97). CONCLUSIONS: African-American/White differences in CRC risk are likely due to sociodemographic/cultural factors other than race. IMPACT: A number of modifiable exposures could be a focus for reducing CRC risk in African-Americans.

Purpose: Renal angiomyolipoma (AML) is a benign neoplasm with a propensity to bleed proportional to tumor size. Transarterial embolization prevents hemorrhage by decreasing the angiogenic component of AML. We sought to determine whether baseline vascularity and lipid content of AML measured by MRI techniques can predict embolization response, as measured by changes in volume and vascularity on MRI. Materials and Methods: A retrospective review using an electronic database, over a consecutive 3 year period, identified 38 AMLs that underwent embolization in 22 patients. 15 AMLs had both preembolization and postembolization MRIs. 11 AMLs were in females, 4 in males. Median age was 29 years, range 21-73 years. 13 AMLs occurred in the setting of tuberous sclerosis (TS), and 2 occurred sporadically. Mean interval between baseline MRI and embolization was 86 days (range 7, 324), and mean interval between embolization and follow-up MRI was 331 days (range 35, 876). Baseline vascularity was measured by percent enhancement, with higher enhancement signifying higher vascularity. Baseline lipid content was measured by AML to psoas signal ratio on T1 fat saturation images, with a higher ratio signifying lower lipid content. Response characteristics were percent change in volume and percent change in enhancement. Results: No correlation was seen between change in volume and change in enhancement (R=0.104). Embolization resulted in a mean change in volume of -28% (range -82,+10), and a mean change in enhancement of -41% (range -97,+17). Poor correlations were seen between baseline enhancement and change in volume (R=-0.033), and between baseline enhancement and change in enhancement (R=-0.345). Moderately good correlations were seen between baseline lipid content and change in volume (R=0.625), and between baseline lipid content and change in enhancement (R=0.463). Conclusion: Embolization is effective in decreasing AML size and vascularity, which can be regarded as independent MRI markers of response. Lower baseline lipid content on MRI may predict greater response to embolization. No significant correlation was detected between baseline vascularity and response

Numerous factors play a part in health disparities. Although health disparities are manifested at the level of the individual, other contexts should be considered when investigating the associations of disparities with clinical outcomes. These contexts include families, neighborhoods, social organizations, and healthcare facilities. This paper reports on health disparities research as a multilevel research domain from the perspective of a large national initiative. The Centers for Population Health and Health Disparities (CPHHD) program was established by the NIH to examine the highly dimensional, complex nature of disparities and their effects on health. Because of its inherently transdisciplinary nature, the CPHHD program provides a unique environment in which to perform multilevel health disparities research. During the course of the program, the CPHHD centers have experienced challenges specific to this type of research. The challenges were categorized along three axes: sources of subjects and data, data characteristics, and multilevel analysis and interpretation. The CPHHDs collectively offer a unique example of how these challenges are met; just as importantly, they reveal a broad range of issues that health disparities researchers should consider as they pursue transdisciplinary investigations in this domain, particularly in the context of a large team science initiative.

The estrogen receptor (ER)alpha is a biologically and clinically important ligand-modulated transcription factor. The F domain of the ERalpha modulates its functions in a ligand-, promoter-, and cell-specific manner. To identify the region(s) responsible for these functions, we characterized the effects of serial truncations within the F domain. We found that truncating the last 16 residues of the F domain altered the activity of the human ERalpha (hERalpha) on an estrogen response element-driven promoter in response to estradiol or 4-hydroxytamoxifen (4-OHT), its sensitivity to overexpression of the coactivator steroid receptor coactivator-1 in mammalian cells, and its interaction with a receptor-interacting domain of the coactivator steroid receptor coactivator-1 or engineered proteins ("monobodies") that specifically bind to ERalpha/ligand complexes in a yeast two-hybrid system. Most importantly, the ability of the ER to induce pS2 was reduced in MDA-MB-231 cells stably expressing this truncated ER vs. the wild-type ER. The region includes a distinctive segment (residues 579-584; LQKYYIT) having a high content of bulky and/or hydrophobic amino acids that was previously predicted to adopt a beta-strand-like structure. As previously reported, removal of the entire F domain was necessary to eliminate the agonist activity of 4-OHT. In addition, mutation of the vicinal glycine residues between the ligand-binding domain and F domains specifically reduced the 4-OHT-dependent interactions of the hERalpha ligand-binding domain and F domains with monobodies. These results show that regions within the F domain of the hERalpha selectively modulate its activity and its interactions with other proteins.

Women with benign breast diseases (BBD), particularly those with lesions classified as proliferative, have previously been reported to be at increased risk for subsequent development of breast cancer (BC). A cohort of 4970 women with biopsy-proven BBD, identified after histopathology review of BBD biopsies, was studied for determination of subsequent development of BC. We report on 4537 eligible women, 28% of whom are African-American, whose BBD mass was evaluable for pathologic assessment of breast tissue. Ascertainment of subsequent progression to BC from BBD was accomplished through examination of the tumor registries of the Henry Ford Health system, the Detroit SEER registry, and the State of Michigan cancer registry. Incidence rates (IR) are reported per 100,000 person years at risk (100 k pyr). Poisson regression models were used to evaluate the association of demographic and lesion characteristics with BC incidence, using person years at the time of BBD diagnosis as the offset variable. The estimated overall BC IR for this cohort is 452 (95% confidence interval [CI] = 394-519) per 100 k pyr. Incidence for women age 50 and older is 80% greater than for younger women (p = 0.007, IRR = 1.8, 95% CI = 1.36-2.36). Neither marital status (p = 0.91, IRR = 0.97, 95% CI = 0.73-1.29) nor race (p = 0.67, IRR = 0.9, 95% CI = 0.54-1.48) is associated with differences in BC IR. Compared with women having nonproliferative lesions, the risk for BC is greater for women with atypical ductal hyperplasia of (IRR = 5.0; 95%CI = 2.26-11.0; p < 0.001) and other proliferative lesions (IR = 1.7, 95% CI = 1.02-2.95; p = 0.04). BC risk for woman with atypical lesions is significantly higher than for women with proliferative lesions without atypia (IRR = 2.58, 95% CI = 1.35-4.90; p = 0.0039). Neither race nor marital status was a factor for BC incidence from BBD in this cohort. Age retained its importance as a predictor of risk. BBD lesion histopathology in the outcome categories of either proliferative without atypia or proliferative with atypia are significant risk factors for BC, even when adjusted for the influence of demographic characteristics. The risks associated with BBD histological classifications were not different across races.

The estrogen receptor (ER), of which there are two forms, ERalpha and ERbeta, is a ligand-modulated transcription factor important in both normal biology and as a target for agents to prevent and treat breast cancer. Crystallographic studies of the ERalpha ligand-binding domain suggest that Leu-536 may be involved in hydrophobic interactions at the start of a helix, "helix 12," that is crucial in the agonist-stimulated activity of ERalpha, as well as in the ability of antagonists to block the activity of ERalpha. We found that certain mutations of Leu-536 increased the ligand-independent activity of ERalpha although greatly reducing or eliminating the agonist activity of 17beta-estradiol (E2) and 4-hydroxytamoxifen (4OHT), on an estrogen response element-driven and an AP-1-driven reporter. The mutations impaired the interaction of the ER ligand-binding domain with the SRC1 receptor-interacting domain in a mammalian two-hybrid system. When tested in the yeast two-hybrid system, mutation of Leu-536 increased the basal reactivity of ERalpha to probes that recognize the agonist-bound conformation but did not significantly alter its reactivity to these probes in the presence of E2. Most interestingly, mutation of Leu-536 reduced the interaction of the 4OHT-bound ERalpha and increased the reactivity of the raloxifene- or ICI 182,780-bound ERalpha, with probes that recognize the 4OHT-bound ERalpha conformation in a yeast two-hybrid system. These results show that Leu-536 is critical in coupling the binding of ligand to the modulation of the conformation and activity of ERalpha.