Estrogen utilization of IGF-1-R and EGF-R to signal in breast cancer cells

Abstract

As breast cancer cells develop secondary resistance to estrogen deprivation therapy, they increase their utilization of non-genomic signaling pathways. Our prior work demonstrated that estradiol causes an association of ERα with Shc, Src and the IGF-1-R. In cells developing resistance to estrogen deprivation (surrogate for aromatase inhibition) and to the anti-estrogens tamoxifen, 4-OHtamoxifen, and fulvestrant, an increased association of ERα with c-Src and the EGF-R occurs. At the same time, there is a translocation of ERα out of the nucleus and into the cytoplasm and cell membrane. Blockade of cSrc with the Src kinase inhibitor, PP-2 causes relocation of ERα into the nucleus. While these changes are not identical in response to each anti-estrogen, ERα binding to the EGF-R is increased in response to 4-OH-Tamoxifen when compared with tamoxifen. The changes in EGF-R interactions with ERα impart an enhanced sensitivity of tamoxifen resistant cells to the inhibitory properties of the specific EGF-R tyrosine kinase inhibitor, AG 1478. However, with long term exposure of tamoxifen-resistant cells to AG 1478, the cells begin to re-grow but can now be inhibited by the IGF-R tyrosine kinase inhibitor, AG 1024. These data suggest that the IGF-R system becomes the predominant signaling mechanism as an adaptive response to the EGF-R inhibitor. Taken together, this information suggests that both the EGF-R and IGF-R pathways can mediate ERα signaling.To further examine the effects of fulvestrant on ERα function, we examined the acute effects of fulvestrant, on non-genomic functionality. Fulvestrant enhanced ERα association with the membrane IGF-1 receptor (IGF-1R). Using siRNA or expression vectors to knock-down or knock-in selective proteins, we further demonstrated that the ERα/IGF-1R association is Src-dependent. Fulvestrant rapidly induced IGF-1R and MAPK phosphorylation. The Src inhibitor PP2 and IGF-1R inhibitor AG1024 greatly blocked fulvestrant-induced ERα/IGF-1R interaction leading to a further depletion of total cellular ERα induced by fulvestrant and further enhanced fulvestrant-induced cell growth arrest. More dramatic was the translocation of ERα to the plasma membrane in combination with the IGF-1-R as shown by confocal microscopy. Taken in aggregate, these studies suggest that secondary resistance to hormonal therapy results in usage of both IGF-R and EGF-R for non-genomic signaling.

Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma

“…Interaction of IGF1R and ER has been shown in numerous studies, but this interaction also involves physical co-localization. Reported co-localization of the ER, which is generally localized in the nucleus, with IGF1R at the cell membrane underscores the diversity of receptor localization [35]. Taken together, these data suggest that protein localization of tyrosine kinase receptors is a highly dynamic biological process.…”

“…Confocal microscopy images studying subcellular localization of IGF1R show cytoplasmic staining [35,36]. Some have reported cytoplasmic IGF1R staining by IHC [37,38], while others have chosen to ignore cytoplasmic staining, although endoplasmatic staining had been present [39].…”

Epithelial to Mesenchymal Transition Promotes Breast Cancer Progression via a Fibronectin-dependent STAT3 Signaling Pathway

“…Other potentially critical factors that may be relevant in TNBC include the interplay between EGFR and insulin-like growth factor receptor signaling systems and production of cell surface effectors such as the subclass of heparin sulfate proteoglycans known as syndecans (52)(53)(54)(55)(56). Understanding how these different factors are integrated to drive metastatic progression will provide the Somewhat surprisingly, our data also appear to exclude a role for autocrine IL-6 because EMT programs fail to diminish the ability of NME cells to activate STAT3 in response to exogenous IL-6.…”

Mechanics behind Breast Cancer Prevention - Focus on Obesity, Exercise and Dietary Fat

“…For example, IGF-2 is recognized by IGF-1R and activates both estrogen receptor-alpha and estrogen receptor-beta (Richardson et al, 2011). Additionally, Song et al (2010) demonstrated that estrogen can utilize either the IGF-1R or the estrogen receptor (Song et al, 2010). These underlying mechanisms, especially their link to estrogen, may help us better understand the controversy of premenopausal obesity-related breast cancer.…”