CXCR4 Signaling and its Impact on Tumor Progression and Metastasis in Breast Cancer

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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m6A-induced LINC00958 promotes breast cancer tumorigenesis via the miR-378a-3p/YY1 axis

Cell Death Discovery ◽

10.1038/s41420-020-00382-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dongwen Rong ◽

Qian Dong ◽

Huajun Qu ◽

Xinna Deng ◽

Fei Gao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Human Breast Cancer ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Human Breast ◽

Transcript Stability ◽

Rna Transcript ◽

Insight Into ◽

Competitive Endogenous Rna

AbstractIncreasing evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in human breast cancer (BC) tumorigenesis. However, the mechanisms by which lncRNA and N6-methyladenosine (m6A) regulate BC tumorigenesis are still unclear. In the present research, LINC00958 was markedly overexpressed in BC tissue and cells, and LINC00958 upregulation promoted the tumor progression of BC cells. Mechanistically, m6A methyltransferase-like 3 (METTL3) gave rise to the upregulation of LINC00958 by promoting its RNA transcript stability. Moreover, LINC00958 acted as a competitive endogenous RNA for miR-378a-3p to promote YY1. Overall, these data provide novel insight into how m6A-mediated LINC00958 regulates BC tumorigenesis.

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Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22041918 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1918

Author(s):

Mio Yamaguchi ◽

Kiyoshi Takagi ◽

Koki Narita ◽

Yasuhiro Miki ◽

Yoshiaki Onodera ◽

...

Keyword(s):

Breast Cancer ◽

Breast Carcinoma ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Human Breast Carcinoma ◽

Breast Cancer Patients ◽

Breast Carcinomas ◽

Human Breast

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.

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