A Comprehensive Analysis of CXCL12 Isoforms in Breast Cancer1,2

Abstract

CXCL12-CXCR4-CXCR7 signaling promotes tumor growth and metastasis in breast cancer. Alternative splicing of CXCL12 produces isoforms with distinct structural and biochemical properties, but little is known about isoform-specific differences in breast cancer subtypes and patient outcomes. We investigated global expression profiles of the six CXCL12 isoforms, CXCR4, and CXCR7 in The Cancer Genome Atlas breast cancer cohort using next-generation RNA sequencing in 948 breast cancer and benign samples and seven breast cancer cell lines. We compared expression levels with several clinical parameters, as well as metastasis, recurrence, and overall survival (OS). CXCL12-α, -β, and -γ are highly co-expressed, with low expression correlating with more aggressive subtypes, higher stage disease, and worse clinical outcomes. CXCL12-δ did not correlate with other isoforms but was prognostic for OS and showed the same trend for metastasis and recurrence-free survival. Effects of CXCL12-δ remained independently prognostic when taking into account expression of CXCL12,CXCR4, and CXCR7. These results were also reflected when comparing CXCL12-α, -β, and -γ in breast cancer cell lines. We summarized expression of all CXCL12 isoforms in an important chemokine signaling pathway in breast cancer in a large clinical cohort and common breast cancer cell lines, establishing differences among isoforms in multiple clinical, pathologic, and molecular subgroups. We identified for the first time the clinical importance of a previously unstudied isoform, CXCL12-δ.

Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer

“…MELK gene expression was correlated to every sequenced gene in the TCGA breast dataset and genes that were significantly positively or negatively correlated with MELK expression were retained within the gene set. These gene lists were then input into GSEA as described previously (32). GSEA identified that of the top 10 nominated positively associated concepts, three were DNA damage-related, and four were cell-cycle regulation-related (Supplementary Fig.…”

Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts

“…ACKR3 is overexpressed in >30% of all breast cancers (including in situ and invasive ductal and lobular carcinomas), with 97% of studied specimens (106 of 109) exhibiting robust vascular ACKR3 staining with undetectable expression in normal breast tissues (10,15). This overexpression is correlated with poor overall survival and lung metastasis-free survival in patients with invasive ductal carcinomas as well as reduced relapse-free survival in patients with ER+ breast cancer (14,16).…”

CXCL12 (chemokine (C-X-C motif) ligand 12)

“…In a recent study, the expression profiles of the six CXCL12 isoforms and both receptors have been investigated in a large clinical cohort and common breast cancer cell lines. As result, isoform-specific differences in expression and breast cancer outcomes have been established, while CXCR4 and CXCR7 showed an opposite pattern in cancer as compared with normal and further differences between hormone receptor status and molecular subtypes (Zhao et al, 2014).…”