Caveolin-1 regulates EGFR signalling in MCF-7 breast cancer cells and enhances gefitinib-induced tumor cell inhibition

Abstract

Caveolin-1, an essential protein constituent of caveolae, is involved in cell signaling through its association with various signaling molecules. Epidermal growth factor receptor (EGFR) interacts directly with caveolin-1 and this interaction functionally regulates EGFR tyrosine kinase activity. In this report we investigated the role of caveolin-1 overexpression on EGFR signaling in MCF-7 breast cancer cell line. We demonstrate here that although total EGFR expression levels are similar, EGFR phosphorylation is diminished in MCF-7/CAV1 cells compared to parental MCF-7 cells. In addition, MCF-7/CAV1 cells exhibit higher total and activated Akt levels. Moreover, MCF-7/CAV1 cells stimulated with EGF display higher EGFR and Akt phosphorylation associated with enhanced proliferative and motility rates, compared to MCF-7 cells. Pretreatment with gefitinib inhibits EGF-induced stimulation of both EGFR and downstream Akt and MAPK more efficiently in MCF-7/CAV1 than in MCF-7 cells. In accordance, EGF-induced proliferation and migration is more effectively suppressed with gefinitib in MCF-7/CAV1 compared to parental cells. In conclusion these results suggest that caveolin-1 overexpression in MCF-7 breast cancer cell line modulates EGFR activation levels and EGF-induced EGFR signalling. This is associated with enhanced antitumor effects of gefitinib suggesting a role for EGFR inhibition in caveolin-1 overexpressing breast cancers.

Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor–mediated upregulation of caveolin-1

“…We show here that HIF-dependent overexpression of CAV1 promotes EGFR signaling in CCRCC. Interestingly, gefitinib, an EGFR-specific inhibitor, inhibited the proliferation of MCF-7/ CAV1 breast cancer cells more efficiently than it prohibited the proliferation of MCF-7 parental cells (46). This finding suggests that gefitinib may have beneficial effect on CCRCC displaying a CAV1 overexpression signature.…”

“…For example, under conditions of oxidative stress, CAV1 was shown to transport EGFR to a perinuclear location where EGFR no longer is degraded and remains active (42). CAV1-overexpressing MCF-7 breast cancer cells (MCF-7/CAV1) stimulated with EGF displayed higher EGFR signaling, with enhanced proliferative and motility rates, than seen in MCF-7 parental cells (43). These examples of differential roles of CAV1 in the regulation of EGFR also may suggest the cell contextdependent nature of CAV1 function.…”

A Novel Taspine Derivative, HMQ1611, Inhibits Breast Cancer Cell Growth via Estrogen Receptor α and EGF Receptor Signaling Pathways

“…Cell viability was measured using WST-1, an antiproliferative assay. MCF-7 and ZR-75-30 cells are positively expressed ERa whereas MDA-MB-231 and SK-BR-3 cell are not (38)(39)(40)(41)(42)(43). HMQ1611 decreased the cell viabilities of the 4 types of cancer cells (Fig.…”

“…In our laboratory, cell morphology, growth curve, and mycoplasma contamination were regularly checked to ensure the absence of contamination during the culture. MCF-7 and ZR-75-30 are ERa-positive expression cell lines (38)(39)(40)(41). SK-BR-3 and MDA-MB-231 are ERa-negative cell lines (42,43 …”

Caveolin-1 Is Required for Kinase Suppressor of Ras 1 (KSR1)-Mediated Extracellular Signal-Regulated Kinase 1/2 Activation, H-RasV12-Induced Senescence, and Transformation

“…Caveolin-1 recruits and organizes H-Ras, Raf, MEK, and ERK to caveola membranes (25,(38)(39)(40) and regulates activation of Raf, MEK, and ERK by growth factors or the Ras oncogene (14,22,24,41,42). KSR1 localizes to the plasma membrane upon activation of the Raf/MEK/ERK kinase cascade (43).…”