It has been recently identified that the CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis, especially in directing metastatic cancer cells to CXCL12-riched organs and tissues.
LRP6N might be a promising diagnostic marker for the early detection of breast cancer metastasis as well as an inhibitor of SDF-1/CXCR4-induced breast cancer metastasis.
The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases.
Increased expression of chemokines like CXCL12 and dysregulated signaling intermediates such as Notch in patients with solid tumors (e.g., breast cancer) is associated with brain metastasis.
Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese.
CXCR4 was more expressed in PT than in metastases (p = 0.0067), whereas CXCL12 was highly expressed in metastatic lesions located in liver and lung (p < 0.0001), as reported for human breast cancer.
These results suggest a key role for the CXCR4-CXCL12 chemokine axis in breast cancer progression and highlight the prognostic importance of this chemokine axis for breast cancer survival.
High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival.
More importantly, LYG-202 also inhibited tumor angiogenesis and tumor growth of human breast cancer MDA-MB-231 cells in nude mice through CXCL12/CXCR7 pathway.
Furthermore, we described for the first time pro-angiogenic effects of Pit-1 through the CXCL12-CXCR4 axis, and that extravasation of Pit-1 overexpressing breast cancer cells is strongly reduced in CXCL12-deprived target tissues.
Furthermore, higher CXCL12/SDF1 protein expression was associated with positive ER status (OR, 1.92; 95% CI, 1.08-3.45; P = .03), negative HER2 status (OR, 2.64; 95% CI, 1.06-6.59; P = .04), and small tumor size (OR, 2.49; 95% CI, 1.47-4.22; P = .0007) in breast cancer, respectively.
Furthermore, <i>in-silico</i> approaches were adapted to investigate the association of CXCL12 and its receptor CXCR4 with genes/proteins involved in BC signalling.
Moreover, E2, TCS, and BPA increased the protein expression of CXCR4, which is a receptor of chemokine CXCL12 that is positively involved in breast cancer metastasis via an ER-dependent pathway.
On subgroup analysis by cancer type, high CXCL12 expression was associated with reduced overall survival in patients with oesophagogastric (HR 2.08; 95% CI: 1.31-3.33, P=0.002), pancreatic (HR 1.54; 95% CI: 1.21-1.97, P=0.0005) and lung cancer (HR 1.37; 95% CI: 1.08-1.75, P=0.01), whereas in breast cancer patients high CXCL12 expression conferred an overall survival advantage (HR 0.5; 95% CI: 0.38-0.66, P<0.00001).
Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome.
In this study, we demonstrated the significant inhibitory effects of a novel chemically synthetic peptide (E5) on the CXCR4/CXCL12 axis in breast cancer both <i>in vitro</i> and <i>in vivo</i>.
NT21MP, a 21-residue peptide derived from the viral macrophage inflammatory protein II, competed effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in breast cancer.