Differential Estrogen-Regulation of CXCL12 Chemokine Receptors, CXCR4 and CXCR7, Contributes to the Growth Effect of Estrogens in Breast Cancer Cells

Abstract

CXCR4 and CXCR7 are the two receptors for the chemokine CXCL12, a key mediator of the growth effect of estrogens (E2) in estrogen receptor (ER)-positive breast cancers. In this study we examined E2-regulation of the CXCL12 axis components and their involvement in the growth of breast cancer cells. CXCR4 and CXCR7 were differentially regulated by E2 which enhanced the expression of both CXCL12 and CXCR4 but repressed the expression of CXCR7. Formaldehyde-associated isolation of regulatory elements (FAIRE) revealed that E2-mediated transcriptional regulation of these genes is linked to the control of the compaction state of chromatin at their promoters. This effect could be accomplished via several distal ER-binding sites in the regions surrounding these genes, all of which are located 20–250 kb from the transcription start site. Furthermore, individual down-regulation of CXCL12, CXCR4 or CXCR7 expression as well as the inhibition of their activity significantly decreases the rate of basal cell growth. In contrast, E2-induced cell growth was differentially affected. Unlike CXCR7, the inhibition of the expression or activity of either CXCL12 or CXCR4 significantly blunted the E2-mediated stimulation of cellular growth. Besides, CXCR7 over-expression increased the basal MCF-7 cell growth rate and decreased the growth effect of E2. These findings indicate that E2 regulation of the CXCL12 signaling axis is important for the E2-mediated growth effect of breast cancer cells. These data also provide support for distinct biological functions of CXCR4 and CXCR7 and suggest that targeting CXCR4 and/or CXCR7 would have distinct molecular effects on ER-positive breast tumors.

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…Whereas the molecular mechanisms through which ACKR3 influences α 1 -AR function remain to be determined, the observed effects of ubiquitin in the present study are in agreement with the findings that ubiquitin functions as a noncognate CXCR4 agonist that does not bind to ACKR3 (51,52,(59)(60)(61)(62)(63). The observation that CXCL12, which has a much higher affinity for ACKR3 than for CXCR4 (64), also enhanced the potency of PE in normal animals in vivo in the present study, whereas CXCL12 previously desensitized PE-mediated vasoconstriction of isolated arteries and reduced blood pressure during hemorrhagic shock (9), suggests that effects of CXCL12 depend on the relative functional contribution of CXCR4 and ACKR3 within the specific experimental or (patho)physiological environment (65).…”

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

“…In different systems, including breast cancer [17-22], it has been reported that CXCL12 can act in an autocrine manner, through its two cognitive receptors CXCR4 and CXCR7. Previous work has shown that estrogen induces both CXCL12 and its receptor CXCR4 in breast cancer and this mechanism is critical for their pro-proliferative and pro-migratory effect in breast cancer [17-22].…”

“…It has therefore been suggested that CXCR4 could be a novel molecular diagnostic and therapeutic target in breast cancer patients [16]. The relation of estrogen and ERs with CXCL12 and CXCR4 in breast cancer cell proliferation and metastatic potential has been examined in depth during the last decade [17-22]. However, only a few reports have investigated the possible interaction between androgen/AR and CXCL12 and its receptors, mostly describing pro-migratory effects in prostate cancer [23-26].…”

Insights into the mechanism of CXCL12-mediated signaling in trophoblast functions and placental angiogenesis

“…2). Additionally, numerous tumor-related studies have indicated that CXCL12 and CXCR4 are involved in the growth and vasculogenesis of tumor tissues such as endometrial carcinoma, ovarian cancer, and breast cancer [65][66][67]. This evidence encourages us to reflect on the role of the CXCL12/CXCR4 axis in utero-placental blood vessel remodeling.…”

“…Notably, CXCR4 and CXCR7 are differentially regulated by estrogen. Estrogen enhances the expressions of both CXCL12 and CXCR4, but inhibits CXCR7 expression, further suggesting distinct biological functions for CXCR4 and CXCR7 [66]. Furthermore, CXCL12/CXCR4 signaling can increase ER transcriptional activity and activate ERα and ERβ, which further promotes the estrogen-mediated signaling pathways [82].…”