Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults over 50 years old. Genetic, epidemiological, and molecular studies are beginning to unravel the intricate mechanisms underlying this complex disease, which implicate the lipid-cholesterol pathway in the pathophysiology of disease development and progression. Many of the genetic and environmental risk factors associated with AMD are also associated with other complex degenerative diseases of advanced age, including cardiovascular disease (CVD). In this review, we present epidemiological findings associating AMD with a variety of lipid pathway genes, cardiovascular phenotypes, and relevant environmental exposures. Despite a number of studies showing significant associations between AMD and these lipid/cardiovascular factors, results have been mixed and as such the relationships among these factors and AMD remain controversial. It is imperative that researchers not only tease out the various contributions of such factors to AMD development but also the connections between AMD and CVD to develop optimal precision medical care for aging adults.

14-3-3 proteins are a family of structurally similar phospho-binding proteins that regulate essentially every major cellular function. Decades of research on 14-3-3s have revealed a remarkable network of interacting proteins that demonstrate how 14-3-3s integrate and control multiple signaling pathways. In particular, these interactions place 14-3-3 at the center of the signaling hub that governs critical processes in cancer, including apoptosis, cell cycle progression, autophagy, glucose metabolism, and cell motility. Historically, the majority of 14-3-3 interactions have been identified and studied under nutrient-replete cell culture conditions, which has revealed important nutrient driven interactions. However, this underestimates the reach of 14-3-3s. Indeed, the loss of nutrients, growth factors, or changes in other environmental conditions (e.g., genotoxic stress) will not only lead to the loss of homeostatic 14-3-3 interactions, but also trigger new interactions, many of which are likely stress adaptive. This dynamic nature of the 14-3-3 interactome is beginning to come into focus as advancements in mass spectrometry are helping to probe deeper and identify context-dependent 14-3-3 interactions—providing a window into adaptive phosphorylation-driven cellular mechanisms that orchestrate the tumor cell’s response to a variety of environmental conditions including hypoxia and chemotherapy. In this review, we discuss emerging 14-3-3 regulatory mechanisms with a focus on post-translational regulation of 14-3-3 and dynamic protein–protein interactions that illustrate 14-3-3’s role as a stress-adaptive signaling hub in cancer.

We have examined the ability of 17beta-estradiol (E2) to induce development of mammary cancers in the female ACI rat. Continuous treatment with E2, delivered through release from s.c. Silastic tubing implants containing 27.5 mg crystalline hormone, resulted in rapid development of palpable mammary tumors in ovary-intact ACI rats. In a population of 21 E2-treated rats, palpable tumors were first observed following 99 days treatment and 100% of the treated population developed tumors within 197 days. The median and mean times to appearance of first palpable tumor were 143 and 145 days respectively. All mammary tumors were classified as carcinomas and invasive features were observed. Circulating E2 levels in the treated animals at the time of sacrifice averaged 185 pg/ml serum. Mammary tumors were not observed in ovary-intact female ACI rats that were not treated with E2. This is the first report indicating that this naturally occurring estrogen is capable of inducing mammary cancers in the ACI rat strain. Mammary carcinoma did not develop in a population of 11 ovariectomized female ACI rats treated with E2 for a period of 140 days. Circulating E2 levels in the treated ovariectomized animals averaged 207 pg/ml. These data indicate that the ovary modulates estrogen-mediated mammary carcinogenesis in this rat strain. Both ovary-intact and ovariectomized female ACI rats displayed similar susceptibilities to E2-induced pituitary tumors and hyperprolactinemia. Pituitary weight was increased 6.0-fold in ovary-intact ACI rats and 5.3-fold in ovariectomized female rats. Circulating prolactin levels averaged 2318 ng/ml in E2-treated, ovary-intact rats and 2285 ng/ml in E2-treated, ovariectomized ACI rats. These data indicate that estrogen-induced hyperprolactinemia is not the sole factor leading to development of mammary cancers in the E2-treated ACI rat.

Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17B-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN Â ACI)F 2 rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN Â ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions. (Cancer Res 2006; 66(15): 7793-800)