Immunohistochemical Expression of CXCR4 on Breast Cancer and Its Clinical Significance

Abstract

Many tumor cells express chemokines and chemokine receptors, and, for this reason, these molecules can affect the tumor progression. It is known that breast cancer is a complex and heterogeneous neoplasia comprising distinct diseases, histological characteristics, and clinical outcomes. The most studied role for CXCL12 chemokine and its receptor CXCR4 in breast cancer pathogenesis is the metastasis event, although several reports have demonstrated its involvement in other processes, such as angiogenesis and tumor growth. It has been found that CXCR4 is required for breast cancer cell migration to other sites such as lung, bone, and lymph nodes, which express high levels of CXCL12 chemokine. Therefore, CXCR4 is being considered a prognostic marker in breast cancer. Within this context, this review summarizes established studies involving expression of CXCR4 on breast cancer, focusing on its clinical significance.

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

“…Recently, we and others reported that stimulation of the GPCR CXCR4 by its ligand, chemokine stromal-derived factor 1 (SDF-1/CXCL12), induces P-Rex1-dependent Rac1 activation and motility (40,46,47), which is consistent with the well-established role of the SDF-1/CXCR4 pathway in metastatic dissemination (48,49). Indeed, CXCR4 has been functionally linked to breast cancer cell motility, invasion, and metastasis and is considered a marker of poor patient prognosis (50)(51)(52)(53)(54)(55). CXCR4 is also essential for ErbB2-mediated tumor metastasis, and coexpression with ErbB2 and EGFR is predictive of a poor prognosis in breast cancer patients (56,57), arguing for potential functional interrelationships between CXCR4 and ErbB receptors.…”

“…Our results clearly show that prolonged HRG treatment induces the expression of CXCR4 in breast cancer cells, leading to enhanced motility signaling via the P-Rex1/Rac1 pathway in response to activation by its ligand, SDF-1. Early studies reported that CXCR4 is upregulated in breast tumors; moreover, CXCR4 expression is enriched in metastatic breast cancer cells and confers invasive properties, and it is considered a marker of poor patient prognosis (50)(51)(52)(53)(54)(55). The relevance of the SDF-1/CXCR4 axis in metastasis has also been demonstrated in other cancer types, including prostate, lung, and pancreatic cancers (75).…”

“…CXCR4 expression in breast cancer is associated with aggressiveness and a poor prognosis (48)(49)(50)(51)(52)(53)(54)(55). SDF-1 activates the Rac1 small GTPase to promote breast cancer cell motility (40).…”

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

“…CXCL12 actions in breast cancer are associated with cell proliferation, cell migration and the formation of breast cancer metastases [15]. Here, in order to investigate whether enhanced CXCL12 expression, under testosterone treatment, is implicated in an increased metastatic potential of MCF-7 and T47D cells, we treated the two cell lines with testosterone and investigated their proliferation and their motility potential.…”

“…We now know, through the widespread identification of CXCR4 on different solid tumors, including breast cancer, that this system controls several critical processes, related to primary tumor development and metastatic potential [15]. CXCR4 is essential for breast cancer cell migration to the lung, bone, and lymph nodes, that express CXCL12 [15].…”