Various miRNAs play critical roles in the development and progression of solid tumors. In this study, we describe the role of miR-204-5p in limiting growth and progression of breast cancer. In breast cancer tissues, miR-204-5p was significantly downregulated compared with normal breast tissues, and its expression levels were associated with increased survival outcome in patients with breast cancer. Overexpression of miR-204-5p inhibited viability, proliferation, and migration capacity in human and murine breast cancer cells. In addition, miR-204-5p overexpression resulted in a significant alteration in metabolic properties of cancer cells and suppression of tumor growth and metastasis in mouse breast cancer models. The association between miR-204-5p expression and clinical outcomes of patients with breast cancer showed a nonlinear pattern that was reproduced in experimental assays of cancer cell behavior and metastatic capacities. Transcriptome and proteomic analysis revealed that various cancer-related pathways including PI3K/Akt and tumor-immune interactions were significantly associated with miR-204-5p expression. PIK3CB, a major regulator of PI3K/ Akt pathway, was a direct target for miR-204-5p, and the association between PIK3CB-related PI3K/Akt signaling and miR-204-5p was most evident in the basal subtype. The sensitivity of breast cancer cells to various anticancer drugs including PIK3CB inhibitors was significantly affected by miR-204-5p expression. In addition, miR-204-5p regulated expression of key cytokines in tumor cells and reprogrammed the immune microenvironment by shifting myeloid and lymphocyte populations. These data demonstrate both cellautonomous and non-cell-autonomous impacts of tumor suppressor miR-204-5p in breast cancer progression and metastasis.Significance: This study demonstrates that regulation of PI3K/Akt signaling by miR-204-5p suppresses tumor metastasis and immune cell reprogramming in breast cancer.

Resistance to chemotherapeutic agents has been considered as a major reason for the high incidence rate of recurrence and metastasis suffered by colorectal cancer (CRC) patients. ATP-binding cassette sub-family G member 2 (ABCG2) is involved in drug resistance. DNA methylation of the ABCG2 promoter site has a significant influence on the regulation of epigenetic gene expression. In the present study, we investigated whether the methylation status of the ABCG2 promoter is related to drug sensitivity in CRC cell lines. In order to examine the ABCG2 expression level and identify the methylation status, RT-PCR, qRT-PCR analysis, MS-PCR and bisulfite sequencing were conducted on 32 CRC cell lines. SNU-C4, LS174T and NCI-H716 were selected as low ABCG2-expressing and high promoter methylated cell lines. The cell proliferation assay for 5-fluorouracil, oxaliplatin and irinotecan was performed after 5-aza-2'-deoxycytidine (5-aza) treatment in these cell lines. In the 32 CRC cell lines, 25% of the cell lines expressed low or no ABCG2 expression. Of these cell lines, SNU-C4, LS174T and NCI-H716 were hypermethylated at the promoter region, ~20%. Demethylation of ABCG2 was induced by 5-aza, which enhanced the ABCG2 expression level and influenced the cell proliferation similar to treatment with the anticancer agents. Our data suggest that the ABCG2 expression level regulated by methylation is related to anticancer drug sensitivity. Based on these results, it can be applied to predict the anticancer drug response.

Each breast cancer has its unique spatial shape, but the clinical importance and the underlying mechanism for the three-dimensional tumor shapes are mostly unknown. We collected the data on the three-dimensional tumor size and tumor volume data of invasive breast cancers from 2,250 patients who underwent surgery between Jan 2000 and Jul 2007. The degree of tumor eccentricity was estimated by using the difference between the spheroid tumor volume and ellipsoid tumor volume (spheroid-ellipsoid discrepancy, SED). In 41 patients, transcriptome and exome sequencing data obtained. Estimation of more accurate tumor burden by calculating ellipsoid tumor volumes did not improve the outcome prediction when compared to the traditional longest diameter measurement. However, the spatial tumor eccentricity, which was measured by SED, showed significant variation between the molecular subtypes of breast cancer. Additionally, the degree of tumor eccentricity was associated with well-known prognostic factors of breast cancer such as tumor size and lymph node metastasis. Transcriptome data from 41 patients showed significant association between MMP13 and spatial tumor shapes. Network analysis and analysis of TCGA gene expression data suggest that MMP13 is regulated by ERBB2 and S100A7A. The present study validates the usefulness of the current tumor size method in determining tumor stages. Furthermore, we show that the tumors with high eccentricity are more likely to have aggressive tumor characteristics. Genes involved in the extracellular matrix remodeling can be candidate regulators of the spatial tumor shapes in breast cancer.

Atopic dermatitis (AD) is a chronic inflammatory skin disease which requires continuous treatment due to its relapsing nature. The current treatment includes steroids and nonsteroidal agents targeting inflammation but long-term administration causes various side effects such as skin atrophy, hirsutism, hypertension and diarrhea. Thus, there is an unmet need for safer and effective therapeutic agents in the treatment of AD. Peptides are small biomolecule drugs which are highly potent and remarkably have less side effects. Parnassin is a tetrapeptide with predicted anti-microbial activity curated from Parnassius bremeri transcriptome data. In this study, we confirmed the effect of parnassin on AD using a DNCB-induced AD mouse model and TNF-α/IFN-γ-stimulated HaCaT cells. In the AD mouse model, topical administration of parnassin improved skin lesions and symptoms in AD mice, such as epidermal thickening and mast cell infiltration, similar to the existing treatment, dexamethasone, and did not affect body weight, or the size and weight of spleen. In TNF-α/IFN-γ-stimulated HaCaT cells, parnassin inhibited the expression of Th2-type chemokine CCL17 and CCL22 genes by suppressing JAK2 and p38 MAPK signaling kinases and their downstream transcription factor STAT1. Parnassin also significantly reduced the gene expression of TSLP and IL-31, which are pruritus-inducing cytokines. These findings suggested that parnassin alleviates AD-like lesions via its immunomodulatory effects and can be used as a candidate drug for the prevention and treatment of AD because it is safer than existing treatments.

Background: Each breast cancer has its unique spatial shape, but the clinical importance and the underlying mechanism for the three-dimensional tumor shapes are mostly unknown. Methods: We collected the data on the three-dimensional tumor size and tumor volume data of invasive breast cancers from 2,250 patients who underwent surgery between Jan 2000 and Jul 2007. The degree of tumor eccentricity was estimated by using the difference between the spheroid tumor volume and ellipsoid tumor volume (spheroid-ellipsoid discrepancy, SED). In 39 patients, transcriptome and exome sequencing data obtained. Results: Estimation of more accurate tumor burden by calculating ellipsoid tumor volumes did not improve the outcome prediction when compared to the traditional longest diameter measurement. However, the spatial tumor eccentricity, which was measured by SED, showed significant variation between the molecular subtypes of breast cancer. Additionally, the degree of tumor eccentricity was associated with well-known prognostic factors of breast cancer such as tumor size and lymph node metastasis. Transcriptome data from 39 patients showed significant association between genes involved in metal/ion binding, nucleotide binding, and extracellular matrix, and the degree of tumor eccentricity. Conclusion: The present study validates the usefulness of the current tumor size method in determining tumor stages. Furthermore, we show that the tumors with high eccentricity are more likely to have aggressive tumor characteristics. Genes involved in the extracellular matrix remodeling are candidate regulators of the spatial tumor shapes in breast cancer. Citation Format: Hyeong-Gon Moon, Namshin Kim, Minju Lee, HyunHye Moon, Tae-Kyung Yoo, Han-Byoel Lee, Jisun Kim, Dong-Young Noh, Wonshik Han. The clinical significance and molecular features of the spatial tumor shapes in breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B60.