MicroRNAs (miRs) are a critical class of small (21–25 nucleotides) non-coding endogenous RNAs implicated in gene expression regulation. We identified miR-23b and miR-27b as miRNAs that are highly upregulated in human breast cancer. We found that engineered knockdown of miR-23b and miR-27b substantially repressed breast cancer growth. Nischarin (NISCH) expression was augmented by knockdown of miR-23b as well as miR-27b. Notably, these miRNAs and Nischarin were inversely expressed in human breast cancers, underscoring their biologic relevance. We demonstrated the clinical relevance of the expression of these miRNAs and showed that high expression of miR-23b and miR-27b correlates with poor outcome in breast cancer. Moreover, intraperitoneally delivered anti-miR-27b restored Nischarin expression and decreased tumor burden in a mouse xenograft model of human mammary tumor. Also we report for the first time that HER2/neu (ERBB2), EGF, and TNFA promote miR-23b/27b expression through the AKT/NF-κB signaling cascade. Nischarin was found to regulate miR-27b/23b expression through a feedback loop mechanism by suppressing NF-κB phosphorylation. Since anti-miR-27b compounds that suppress miR-27b inhibit tumor growth, the anti-miR-27b appears to be a good candidate for the development of new anti-tumor therapies.

Nischarin may be a novel tumor suppressor that limits breast cancer progression by regulating α5 integrin expression and subsequently α5 integrin-, FAK-, and Rac-mediated signaling.

Increased expression of the full-length androgen receptor (AR-FL) and AR splice variants (AR-Vs) drives the progression of castration-resistant prostate cancer (CRPC). The levels of AR-FL and AR-V transcripts are often tightly correlated in individual CRPC samples, yet our understanding of how their expression is co-regulated is limited. Here, we report a role of c-Myc in accounting for coordinated AR-FL and AR-V expression. Analysis of gene expression data from 159 metastatic CRPC samples and 2142 primary prostate tumors showed that the level of c-Myc is positively correlated with that of individual AR isoforms. A striking positive correlation also exists between the activity of the c-Myc pathway and the level of individual AR isoforms, between the level of c-Myc and the activity of the AR pathway, and between the activities of the two pathways. Moreover, the c-Myc signature is highly enriched in tumors expressing high levels of AR, as is the AR signature in c-Myc-high-expressing tumors. Using shRNA knockdown, we confirmed c-Myc regulation of expression and activity of AR-FL and AR-Vs in cell models and a patient-derived xenograft model. Mechanistically, c-Myc promotes the transcription of the AR gene and enhances the stability of the AR-FL and AR-V proteins without altering AR RNA splicing. Importantly, inhibiting c-Myc sensitizes enzalutamide-resistant cells to growth inhibition by enzalutamide. Overall, this study highlights a critical role of c-Myc in regulating the coordinated expression of AR-FL and AR-Vs that is commonly observed in CRPC and suggests the utility of targeting c-Myc as an adjuvant to AR-directed therapy.

Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC.

Metabolic syndrome, which can include weight gain and central obesity, elevated serum insulin and glucose, and insulin resistance, has been strongly associated with breast cancer recurrence and worse outcomes after treatment. Epidemiologic and prospective data do not show conclusive evidence as to which dietary factors may be responsible for these results. Current strategies employ low-fat diets which emphasize supplementing calories with increased intake of fruit, grain, and vegetable carbohydrate sources. Although results thus far have been inconclusive, recent randomized trials employing markedly different dietary strategies in noncancer patients may hold the key to reducing multiple risk factors in metabolic syndrome simultaneously which may prove to increase the long-term outcome of breast cancer patients and decrease recurrences. Since weight gain after breast cancer treatment confers a poor prognosis and may increase recurrence rates, large-scale randomized trials are needed to evaluate appropriate dietary interventions for our breast cancer patients.

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CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

Caloric restriction has been shown to increase lifespan in several organisms and to delay onset of age-related diseases. The transcriptional response to caloric restriction has been studied for mRnAs, while the microRnA signature following caloric restriction remains unexplored. here, we characterize the microRnA expression in mouse breast tissue before and after caloric restriction, reporting several changes in the microRnA expression profile. In particular, miR-203 is found to be highly induced by caloric restriction, and we demonstrate that caveolin-1 as well as p63 are direct targets of miR-203 in vivo during caloric restriction. Using tissue culture models, we suggest that this regulation is important in both mouse and human. In conclusion, we show that the microRnA response induced by caloric restriction can regulate important factors in processes such as longevity and aging and is an integral and important component of the cellular response to caloric restriction.Caloric restriction (CR) has been shown to have a positive effect on life span across several organisms [1][2][3] and is speculated to be beneficial for the treatment of age-related diseases. Delineating the genetic response to CR is crucial to understand these effects on aging and disease and specifically in breast tissue since CR has been shown to have potential therapeutic benefit in diseases of the breast. 4,5