Nalo Hamilton

Genetic Differences in Human Circadian Clock Genes Among Worldwide Populations

The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.

Shift Work in Nurses: Contribution of Phenotypes and Genotypes to Adaptation

Background Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work. Methods Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses. Results Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work). Conclusions Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental “stress” to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.

Regulation of BRCA2 gene expression by the SLUG repressor protein in human breast cells

The expression of the breast cancer susceptibility protein BRCA2 is highly regulated in human breast, ovary, and pancreatic cells. BRCA2 is not expressed in the non-dividing cells, and expression is cell cycle stage-dependent and is elevated in the sporadic cancer cells. Mutational analysis of the upstream sequence of the human BRCA2 gene revealed an E2-box-containing silencer at the –701 to –921 position. The E2-box is essential for the cell-cycle stage-dependent activity of the silencer. We affinity-purified a 29-kDa silencer-binding protein (SBP) from the nuclear extracts of human breast cells BT-549 and MDA-MB-231. We explored whether the E2-box-binding repressor protein SLUG, which is of similar molecular size, is involved in the silencing process. Supershift assay with the purified SBP and anti-SLUG antibody revealed the identity of the SBP as SLUG. We found that silencer is inactive in the human breast cancer cells such as MDA-MB-468 and MCF-7 that do not express SLUG, further suggesting the involvement of SLUG in the BRCA2 gene silencing. Inducible expression of human SLUG in the dividing MDA-MB-468 cells reduced BRCA2 RNA levels with the activation of the silencer. Furthermore, small interfering RNA-mediated knockdown of SLUG mRNA in the BT-549 cells caused inhibition of the silencer function. Chromatin immunoprecipitation assays suggested that SLUG mediates its action by recruiting C-terminal-binding protein-1 (CtBP-1) and histone deacetylase-1 (HDAC-1) at the silencer E2-box. The general HDAC inhibitor, trichostatin A, inhibited the SLUG-mediated regulation of the silencer function. It thus appears that SLUG is a negative regulator for BRCA2 gene expression.

Biologic Roles of Estrogen Receptor-β and Insulin-Like Growth Factor-2 in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) occurs in 10–15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women. Although initially responsive to some chemotherapies, TNBCs tend to relapse and metastasize. Thus, it is critical to find new therapeutic targets. A second ER gene product, termed ERβ, in the absence of ERα may be such a target. Using human TNBC specimens with known clinical outcomes to assess ERβ expression, we find that ERβ1 associates with significantly worse 5-year overall survival. Further, a panel of TNBC cell lines exhibit significant levels of ERβ protein. To assess ERβ effects on proliferation, ERβ expression in TNBC cells was silenced using shRNA, resulting in a significant reduction in TNBC proliferation. ERβ-specific antagonists similarly suppressed TNBC growth. Growth-stimulating effects of ERβ may be due in part to downstream actions that promote VEGF, amphiregulin, and Wnt-10b secretion, other factors associated with tumor promotion. In vivo, insulin-like growth factor-2 (IGF-2), along with ERβ1, is significantly expressed in TNBC and stimulates high ERβ mRNA in TNBC cells. This work may help elucidate the interplay of metabolic and growth factors in TNBC.

Retention of faculty of color in academic nursing

BACKGROUND Racial and ethnic diversity among nursing faculty is low, preventing schools of nursing (SON) from reflecting the populations that they serve academically and clinically. Few studies address the experience and success of faculty of color (FOC) in nursing. PURPOSE The purpose of this article is to summarize the current literature related to FOC retention and promotion. METHODS We reviewed 25 articles from the nursing literature following PRISMA guidelines, using a critical race theory framework. DISCUSSION We describe barriers and promoters to retention, benefits of retaining FOC, and proposed solutions to FOC attrition. We also highlight polices by several SON that netted increased retention and promotion of nursing FOC. CONCLUSION FOC meet substantial challenges that influence their career pathway. SON can improve faculty retention through focused efforts on improving the institutional culture to promote an inclusive environment.

Extranuclear signaling by sex steroid receptors and clinical implications in breast cancer

Estrogen and progesterone play essential roles in the development and progression of breast cancer. Over 70% of breast cancers express estrogen receptors (ER) and progesterone receptors (PR), emphasizing the need for better understanding of ER and PR signaling. ER and PR are traditionally viewed as transcription factors that directly bind DNA to regulate gene networks. In addition to nuclear signaling, ER and PR mediate hormone-induced, rapid extranuclear signaling at the cell membrane or in the cytoplasm which triggers downstream signaling to regulate rapid or extended cellular responses. Specialized membrane and cytoplasmic proteins may also initiate hormone-induced extranuclear signaling. Rapid extranuclear signaling converges with its nuclear counterpart to amplify ER/PR transcription and specify gene regulatory networks. This review summarizes current understanding and updates on ER and PR extranuclear signaling. Further investigation of ER/PR extranuclear signaling may lead to development of novel targeted therapeutics for breast cancer management.

Biopsychosocial Predictors of Psychological Functioning Among African American Breast Cancer Survivors

This study examined the relationships of biological and psychosocial predictors as contributing factors to the psychological functioning among breast cancer survivors. A sample of (N = 155) African American breast cancer survivors were recruited from California. A general linear model was utilized to examine the relationships. Biological and psychosocial risk factors were significant predictors for anxiety and depression. These predictors can be viewed as contributing factors to the psychological well-being of this cohort. Anxiety and depression are often under-recognized and subsequently undertreated in survivors. Understanding the predictors of depression and anxiety is necessary for incorporating a multidisciplinary approach to address this problem.

Abstract PD03-04: Discovery of metformin derivatives with potent antitumor activity in triple-negative breast cancer

Due to the success of endocrine therapy, the mortality of patients with estrogen receptor-positive tumors has declined significantly in recent years. In contrast, triple-negative breast cancers (TNBC) lack clinical expression of estrogen and progesterone receptors and HER-2 receptor overexpression and cannot be treated with current endocrine or HER2-targeted therapies. TNBC occurs in only 10–15% of patients, yet this disease accounts for a large proportion of all breast cancer deaths. TNBCs are heterogeneous (with most, but not all, categorized as basal-like on gene expression analyses) and occur often in younger and African American women. Although initially responsive to some chemotherapies, TNBCs tend to relapse early and metastasize, leading to poor patient survival. It is urgent to develop new therapeutics. Emerging evidence from epidemiologic and preclinical work suggests that metformin, the most widely used drug to treat type 2 diabetes mellitus, exerts anticancer activity in breast cancer. Diabetic patients treated with metformin have a reduced incidence of and better survival from breast cancer. Moreover, TNBC cells are reportedly uniquely sensitive to metformin, and the antitumor effects of metformin appear to be enhanced at high doses of the drug or by IV administration. Thus, we reason that structural analogs of metformin can be designed and synthesized with even more potent anticancer activity and target specificity than metformin. We now report on development of novel metformin analogues with superior anti-TNBC effects based on preclinical tumor models. We tested metformin and new structural analogues of metformin in TNBC and in estrogen receptor-positive MCF-7 cells. Using cell proliferation assays, cells were treated for 72 hours in the presence of metformin or analogues. Inhibition of cell proliferation was dose-dependant and significant at low concentrations (0.01–1mM) of metformin analogues (P Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-04.

Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) occurs in 10–15% of all breast cancer patients, yet it accounts for about half of all breast cancer deaths. There is an urgent need to identify new antitumor targets to provide additional treatment options for patients afflicted with this aggressive disease. Preclinical evidence suggests a critical role for insulin-like growth factor-2 (IGF2) and androgen receptor (AR) in regulating TNBC progression. To advance this work, a panel of TNBC cell lines was investigated with all cell lines showing significant expression of IGF2. Treatment with IGF2 stimulated cell proliferation in vitro (p < 0.05). Importantly, combination treatments with IGF1R inhibitors BMS-754807 and NVP-AEW541 elicited significant inhibition of TNBC cell proliferation (p < 0.001). Based on Annexin-V binding assays, BMS-754807, NVP-AEW541 and enzalutamide induced TNBC cell death (p < 0.005). Additionally, combination of enzalutamide with BMS-754807 or NVP-AEW541 exerted significant reductions in TNBC proliferation even in cells with low AR expression (p < 0.001). Notably, NVP-AEW541 and BMS-754807 reduced AR levels in BT549 TNBC cells. These results provide evidence that IGF2 promotes TNBC cell viability and proliferation, while inhibition of IGF1R/IR and AR pathways contribute to blockade of TNBC proliferation and promotion of apoptosis in vitro.

Estrogen Receptor-β and the Insulin-Like Growth Factor Axis as Potential Therapeutic Targets for Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBCs) lack estrogen receptor-α (ERα), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) amplification and account for almost half of all breast cancer deaths. This breast cancer subtype largely affects women who are premenopausal, African-American, or have BRCA1/2 mutations. Women with TNBC are plagued with higher rates of distant metastasis that significantly diminish their overall survival and quality of life. Due to their poor response to chemotherapy, patients with TNBC would significantly benefit from development of new targeted therapeutics. Research suggests that the insulin-like growth factor (IGF) family and estrogen receptor beta-1 (ERβ1), due to their roles in metabolism and cellular regulation, might be attractive targets to pursue for TNBC management. Here, we review the current state of the science addressing the roles of ERβ1 and the IGF family in TNBC. Further, the potential benefit of metformin treatment in patients with TNBC as well as areas of therapeutic potential in the IGF-ERβ1 pathway are highlighted.