Insights Gained into the Use of Individual Development Plans as a Framework for Mentoring NIH Postbaccalaureate Research Education Program (PREP) Trainees.

This study examines the use of individual development plans (IDPs) in a structured mentoring program as an effective mechanism for reducing identity-related anxiety for underrepresented trainees and increasing their learner agency. Social cognitive theory served to provide the theoretical framework for our implementation of IDPs and our investigation of the effects of completing IDPs on trainees attaining academic goals and subsequent success in enrolling in competitive PhD programs. Results suggest that IDPs are also an effective tool that can allow faculty mentors to provide the social support necessary for trainees to persist in accomplishing their short- and long-term learning goals. Additionally, trainee self-agency, in the use of the IDP and mentoring, seemed to provide an alternative narrative to ability as a sole predictor of STEM achievement. We also found that IDPs helped foster social support networks, providing stability, predictability, and a sense of belonging. Specifically, IDPs helped foster the emotional and informational support necessary for trainees to persist, despite obstacles, as they strived to attain their learning goals.

MicroRNAs: an emerging science in cancer epigenetics.

MicroRNAs (miRNAs) are remarkable molecules that appear to have a fundamental role in the biology of the cell. They constitute a class of non-protein encoding RNA molecules which have now emerged as key players in regulating the activity of mRNA. miRNAs are small RNAmolecules around 22 nucleotides in length, which affect the activity of specific mRNA, directly degrading it and/or preventing its translation into protein. The science of miRNAs holds them as candidate biomarkers for the early detection and management of cancer. There is also considerable excitement for the use of miRNAs as a novel class of therapeutic targets and as a new class of therapeutic agents for the treatment of cancers. From a clinical perspective, miRNAs can induce a number of effects and may have a diverse application in biomedical research. This review highlights the general mode of action of miRNAs, their biogenesis, the effect of diet on miRNA expression and the impact of miRNAs on cancer epigenetics and drug resistance in various cancers. Further we also provide emphasis on bioinformatics software which can be used to determine potential targets of miRNAs.

Epigenetic reactivation of estrogen receptor-α (ERα) by genistein enhances hormonal therapy sensitivity in ERα-negative breast cancer.

BACKGROUND: Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ERα-positive breast cancer cells. However, the role of GE in ERα-negative breast cancer remains unknown. METHODS: We have evaluated the in vitro and in vivo epigenetic effects of GE on ERα reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR) assay, western-blot assay, immunoprecipitation (ChIP) assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo. RESULTS: We found that GE can reactivate ERα expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ERα-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ERα-dependent cellular responses to activator 17ß-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ERα promoter thereby contributing to ERα reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ERα-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ERα reactivation. CONCLUSIONS: Our studies suggest that soybean genistein can epigenetically restore ERα expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ERα-negative breast cancer which will provide more effective options in breast cancer therapy.

Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

Epigenetic diet: impact on the epigenome and cancer.

A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet'. Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.

Epigenomics of ovarian cancer and its chemoprevention.

Ovarian cancer is a major cause of death among gynecological cancers and its etiology is still unclear. Currently, the two principle obstacles in treating this life threatening disease are lack of effective biomarkers for early detection and drug resistance after initial chemotherapy. Similar to other cancers, the initiation and development of ovarian cancer is characterized by disruption of oncogenes and tumor suppressor genes by both genetic and epigenetic mechanisms. While it is well known that it is challenging to treat ovarian cancer through a genetic strategy due in part to its heterogeneity, the reversibility of epigenetic mechanisms involved in ovarian cancer opens exciting new avenues for treatment. The epigenomics of ovarian cancer has therefore become a rapidly expanding field leading to intense investigation. A review on the current status of the field is thus warranted. In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies.

RB stabilizes XPC and promotes cellular NER.

It has long been thought that the G(1)/S cell cycle checkpoint allows time for DNA repair by delaying S-phase entry. The p53 tumor suppressor pathway regulates the G(1)/S checkpoint by regulating the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), but p53 also regulates the nucleotide excision DNA repair protein XPC. Here, using p53-null cell lines we show that additional mechanisms stabilize XPC protein and promote nucleotide excision repair (NER) in concert with the G(1)/S checkpoint. At least one mechanism to stabilize and destabilize XPC involves ubiquitin-mediated degradation of XPC, as the ubiquitin ligase inhibitor MG-132 blocked XPC degradation. The retinoblastoma protein RB, in its unphosphorylated form actually stabilized XPC and promoted NER as measured by host cell reactivation experiments. The data suggest that XPC protein and XPC-mediated NER are tightly linked to the G(1)/S checkpoint, even in cells lacking functional p53.

The Xpc gene markedly affects cell survival in mouse bone marrow.

The XPC protein (encoded by the xeroderma pigmentosum Xpc gene) is a key DNA damage recognition factor that is required for global genomic nucleotide excision repair (G-NER). In contrast to transcription-coupled nucleotide excision repair (TC-NER), XPC and G-NER have been reported to contribute only modestly to cell survival after DNA damage. Previous studies were conducted using fibroblasts of human or mouse origin. Since the advent of Xpc-/- mice, no study has focused on the bone marrow of these mice. We used carboplatin to induce DNA damage in Xpc-/- and strain-matched wild-type mice. Using several independent methods, Xpc-/- bone marrow was approximately 10-fold more sensitive to carboplatin than the wild type. Importantly, 12/20 Xpc-/- mice died while 0/20 wild-type mice died. We conclude that G-NER, and XPC specifically, can contribute substantially to cell survival. The data are important in the context of cancer chemotherapy, where Xpc gene status and G-NER may be determinants of response to DNA-damaging agents including carboplatin. Additionally, altered cell cycles and altered DNA damage signalling may contribute to the cell survival end point.