BackgroundMembers of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive.MethodsWe investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3 sf/+) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family.ResultsFirst, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3 sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3 sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3 sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3 low relative to those with FOXP3 high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3 sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells.ConclusionsmiR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0858-x) contains supplementary material, which is available to authorized users.

CD24 plays an oncogenic role in the onset and progression of various human cancers, including prostate cancer. In the present study, we identified two linkage disequilibrium blocks with four recombination hotspot motifs in human CD24 locus. To elucidate whether genetic variants of CD24 associated with susceptibility to prostate cancer and its disease status, we conducted a case-control association study with two P170 C/T and P-534 A/C polymorphisms of CD24 in 590 patients with prostate cancer and 590 healthy controls. A significant increased risk of prostate cancer was found in men with the P170T/T genotype over the P170C/C genotype (odd ratio=1.74, 95% confidence interval=1.16–2.63, P=0.008), and in men with the P-534C/C genotype over the P-534A/A genotype (odd ratio=1.47, 95% confidence interval=1.18–2.26, P=0.003). Cochran-Armitage trend analysis showed that the P170T allele was significantly correlated with an increased risk of prostate cancer progression (P = 0.029, trend between genotypes and stages) and this observation was also validated in an independent sample cohort. Next, we found that tumors with P170T or P-534C alleles had more 2-fold increased protein expressions of CD24 as compared to those with P170C or P-534A alleles, respectively. Likewise, tumors with a combination of P170T/T and P-534C/C genotypes were associated with a high mRNA level of CD24. Our data suggest a significant association of CD24 genetic variants with prostate cancer onset and progression, which provides new insight into molecular genetics of prostate cancer; however, these findings need to be validated in multiple independent cohorts.

OBJECTIVE Treatment of degenerative lumbar spine pathologies typically escalates to surgical intervention when symptoms begin to significantly impair patients’ functional status. Currently, surgeons rely on subjective patient assessments through patient-reported outcome measures to estimate the decline in patient wellness and quality of life. In this analysis, the authors sought to use smartphone-based accelerometry data to provide an objective, continuous measurement of physical activity that might aid in effective characterization of preoperative functional decline in different lumbar spine surgical indications. METHODS Up to 1 year of preoperative activity data (steps taken per day) from 14 patients who underwent lumbar decompression and 15 patients who underwent endoscopic lumbar fusion were retrospectively extracted from patient smartphones. A data-driven algorithm was constructed based on 10,585 unique activity data points to identify and characterize the functional decline of patients preceding surgical intervention. Algorithmic estimation of functional decline onset was compared with reported symptom onset in clinical documentation across patients who presented acutely (≤ 5 months of symptoms) or chronically (> 5 months of symptoms). RESULTS The newly created algorithm identified a statistically significant decrease in physical activity during measured periods of functional decline (p = 0.0020). To account for the distinct clinical presentation phenotypes of patients requiring lumbar decompression (71.4% acute and 28.6% chronic) and those requiring lumbar fusion (6.7% acute and 93.3% chronic), a variable threshold for detecting clinically significant reduced physical activity was implemented. The algorithm characterized functional decline (i.e., acute or chronic presentation) in patients who underwent lumbar decompression with 100% accuracy (sensitivity 100% and specificity 100%), while characterization of patients who underwent lumbar fusion was less effective (accuracy 26.7%, sensitivity 21.4%, and specificity 100%). Adopting a less-permissive detection threshold in patients who underwent lumbar fusion, which rendered the algorithm robust to minor fluctuations above or below the chronically decreased level of preoperative activity in most of those patients, increased functional decline classification accuracy of patients who underwent lumbar fusion to 66.7% (sensitivity 64.3% and specificity 100%). CONCLUSIONS In this study, the authors found that smartphone-based accelerometer data successfully characterized functional decline in patients with degenerative lumbar spine pathologies. The accuracy and sensitivity of functional decline detection were much lower when using non–surgery-specific detection thresholds, indicating the effectiveness of smartphone-based mobility analysis in characterizing the unique physical activity fingerprints of different lumbar surgical indications. The results of this study highlight the potential of using activity data to detect symptom onset and functional decline in patients, enabling earlier diagnosis and improved prognostication.

association between surgical costs and outcomes. Although higher cost did not guarantee an ideal outcome, high cost patients generally experienced superior patient reported outcomes and realignment at 2-years. Thus, isolating cost reduction as a public health priority may compromise outcomes in ASD patients.

Our major goal is to determine the role of Chromodomain-helicase-DNA-binding protein 7 during breast cancer (BC) metastasis. This protein is an ATP-dependent nucleosome remodeling factor and is critical for embryonic development in both animal models and human patients. Our most recent studies provide direct evidence suggesting its novel role in repressing BC metastasis. We found that this protein, but not the mRNA, is highly expressed in a low-metastatic breast cancer cell line (Mcf-7), while its expression is much reduced in metastatic cell lines (MDA-MB-468 and MDA-MB-231). Furthermore, this protein is predominantly localized in the cytoplasm of 468 and 231 cells, in contrast to its nuclear localization in Mcf-7 cells. In the cytoplasm of 468 and 231 cells, this protein is colocalized with a lysosome marker, suggesting that in high metastatic BC cells, this protein is exported to the cytoplasm to be degraded in lysosomes. Blocking the activity of lysosomes increased expression of this protein in high metastatic BC cell lines. This result suggests a mechanism accounting for the reduced expression of this protein in high metastatic BC cell lines. To further support the potential clinic relevance of our results, this protein is localized in the nucleus of almost all duct epithelial cells in normal breast tissues; however, in a large portion of epithelial cells of breast tumors, this protein is localized in the cytoplasm. Through reporter and mutagenesis analysis, we identified the nuclear exporting signal (NES) sequence responsible for exporting this protein into cytoplasm. In the next set of experiments, we attempted to determine the function of this gene in BC metastasis. We found that knocking down expression of this gene in 468 cell significantly increased their migration and invasion. We next applied the CRISPR genome editing technique to mutate the critical amino acids within the NES region in the endogenous gene locus and found that the amount of protein in the nucleus is significantly increased compared to wild type cells. Migration/invasion of these cells was also dramatically decreased. At the molecular level, we found that forced expression of this protein in nucleus reduced expression of epithelial markers and increased expression of epithelial-mesenchymal-transition markers. We are now applying ChIP-Seq and RNA-Seq approaches to determine direct regulatory network of this protein in 231 cells. We will further test whether this protein acts through modulating the epigenetic status of the enhancers/promoters to regulate expression of its target genes to repress BC metastasis. In summary, our data collectively suggest that Chromodomain-helicase-DNA-binding protein 7 is a novel epigenetic regulator to repress BC metastasis. To the best of our knowledge, our study represents the first to address the activity of this protein in BC. Note: This abstract was not presented at the meeting. Citation Format: Kenneth Jiao, Yin Peng, Lizhong Wang, Runhua Liu. A novel mechanism for regulation of breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2403. doi:10.1158/1538-7445.AM2017-2403