Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation-dependent mechanisms.

DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown.

ATR inhibition reverses the resistance of homologous recombination deficient MGMT/MMR cancer cells to temozolomide.

The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMT/MMR patients benefit from TMZ treatment, indicating a need for additional patient selection criteria.

The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis.

Background: Oncogene overexpression in primary cells often triggers the induction of a cellular safeguard response promoting senescence or apoptosis. Secondary cooperating genetic events are generally required for oncogene-induced tumorigenesis to overcome these biologic obstacles. We employed comparative genomic hybridization for eight genetically engineered mouse models of mammary cancer to identify loci that might harbor genes that enhance oncogene-induced tumorigenesis.

Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells.

Breast cancer (BC) can recur as metastatic disease many years after primary tumor removal, suggesting that disseminated tumor cells survive for extended periods in a dormant state that is refractory to conventional therapies. We have previously shown that altering the tumor microenvironment through fibrosis with collagen and fibronectin deposition can trigger tumor cells to switch from a dormant to a proliferative state. Here, we used an in vivo preclinical model and a 3D in vitro model of dormancy to evaluate the role of Src family kinase (SFK) in regulating this dormant-to-proliferative switch.

Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFß.

Transforming growth factor (ß1TGFß1) can promote proliferation in late stage cancers but acts as a tumor suppressor in normal epithelial cells and in early stage cancers. Although, the TGFß pathway has been shown to play a key role in tumorigenesis and metastasis, only a limited number of models have been developed to understand this process. Here, we present a novel model system to discern this paradoxical role of TGFß1 using the MDA-MB-231 (MB-231) cell line.

Biochanin A reduces drug-induced p75NTR expression and enhances cell survival: a new in vitro assay for screening inhibitors of p75NTR expression.

Following spinal cord injury (SCI) or peripheral neuropathy, increased levels of the p75(NTR) death receptor initiate the signal transduction cascade leading to cell death. Investigations of compounds that may ameliorate neuronal cell death have largely used rodent models, which are time consuming, expensive, and cumbersome to perform. Previous studies had demonstrated that steroids, particularly dexamethasone and its analog methylprednisolone sodium succinate, exhibit limited neuroprotective effects against neuronal injury.

Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment.

Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy seems to arise from tumor cells that disseminated early in the course of disease but did not develop into clinically apparent lesions. These long-term surviving, disseminated tumor cells maintain a state of dormancy, but may be triggered to proliferate through largely unknown factors. We now show that the induction of fibrosis, associated with deposition of type I collagen (Col-I) in the in vivo metastatic microenvironment, induces dormant D2.

Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis.

Considered a chemopreventive agent, the ability of genistein to modulate the progression of existing prostate cancer (CaP) is not clear. We show here that the consumption of genistein (250 mg/kg diet) by 12-week-old transgenic adenocarcinoma mouse prostate (TRAMP-FVB) mice harboring prostatic intraepithelial neoplasia lesions until 20 weeks of age induces an aggressive progression of CaP, as evidenced by a 16% increase in the number of well-differentiated and poorly differentiated prostates, coinciding with a 70% incidence of pelvic lymph node (LN) metastases as opposed to 0% and 10% in 0 and 1,000 mg/kg groups, concomitant with elevated osteopontin (OPN) expression in prostates and LNs. Equivalent nanomolar (500 nmol/L) concentrations of genistein recapitulated these effects in human PC3 CaP cells as evidenced by increased proliferation, invasion, and matrix metalloproteinase-9 (MMP-9) activity (approximately 2-fold), accompanied by an up-regulation of OPN expression and secretion, compared with vehicle-treated cells.

Genistein induces the metastasis suppressor kangai-1 which mediates its anti-invasive effects in TRAMP cancer cells.

Previous studies demonstrated a direct correlation with loss of kangai-1 (KAI1), a metastasis suppressor, and poor prognosis in human prostate and other cancers. In this study, we have characterized the age-dependent downregulation of KAI1 in the TRAMP model which was reversed when mice were fed a genistein-enriched diet. We demonstrated here that doses of genistein (5 and 10 microM)--achievable by supplement intake--significantly induced the expression of KAI1, both at the mRNA and protein levels (up to 2.

Physiologically achievable concentrations of genistein enhance telomerase activity in prostate cancer cells via the activation of STAT3.

Telomerase contributes to the infinite replicative potential of cancer cells by conferring proliferation and survival through the regulation of growth factors and apoptotic proteins. Although it is generally known that the phytoestrogen, genistein, has telomerase-repressing and anti-proliferative effects on various cancer cells at pharmacological concentrations, we report here that physiologically achievable concentrations of genistein enhance telomerase activity, the proliferation of human prostate cancer cells and tumor growth in the transgenic adenocarcinoma mouse prostate model. In determining the mechanism for enhanced telomerase activity, we observed that physiological concentrations of genistein activated signal transducers and activators of transcription 3 (STAT3) both in vitro and in vivo and increased STAT3 binding to the telomerase reverse transcriptase promoter in human prostate cancer cells.

Akt GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype.

Anti-proliferative properties of genistein in prostate and other cancers have been studied extensively. However, the identification of genistein targets that may mediate its chemopreventive effects in vivo requires further elucidation. In this study, we have demonstrated that the incorporation of genistein in the diet of transgenic adenocarcinoma mouse prostate model (TRAMP/FVB) mice resulted in a reduction in prostate size and the incidence of poorly differentiated (PD) cancer ensuing in an accumulation of prostates at the prostatic intra-epithelial neoplasia (PIN) stage.

Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein.

Background: The G2/M cell-cycle arrest is one mechanism by which genistein exerts its anti-proliferative effects, and the proposed underlying causes encompass the transcriptional repression of cyclin B1 and the activation of p21. However, the involvement of upstream kinases Myt-1 and Wee-1 in this arrest remains to be elucidated.

Methods: Myt-1 and Wee-1 modulation by genistein was examined via Western blot analysis and the effect of their inhibition by siRNA on cyclin B1 levels/localization, cdc2 kinase activity, and cellular proliferation of genistein-treated TRAMP-C2 cells was determined.