Article Figures & Data
Figures
- Fig. 1.
A representation of the structural domains, the sites of post-translational modifications, and mutations within ERα. Growth factor signaling leads to numerous downstream phosphorylation events located within the AF-1, DBD, and hinge domains, thus affecting ERα signaling through the “nonclassical” signaling pathways. Post-translational modifications located within the HBD/AF-2 domain affect the “classical” signaling pathway of ERα. In the AF-1 domain, S118 and S167 are phosphorylated by Erk1/2 and Akt, respectively, in the hinge domain, S305 by Akt, PKA, and PAK-1. Phosphorylation of these three sites regulates both ERα's sensitivity to tamoxifen as well as ligand-independent activation of the receptor. Acetylation at residues K266/8, K299, and K302/3 by p300 also modulates ERα activation. A somatic mutation, K303R, allows ERα to be more highly phosphorylated by PKA and Akt, resulting in estrogen hypersensitivity and endocrine resistance. Methylation, occurring by Set7 interaction with ERα, causes increased receptor stability and a heightened recruitment of ERα to its target genes. In the AF-2 domain, the Y537 site is target of c-Src. The Y537N mutation eliminates this phosphorylation site, resulting in constitutive receptor activity. ERα can also be modified by alternative splicing at the DNA level, resulting in exon skipping and a truncated protein with a subsequently altered function. For example, in ERα Δ3, the third exon is alternatively spliced resulting in a truncated DBD. This isoform does not bind to DNA and is a dominant negative inhibitor to the wild-type ERα. Another truncated ERα isoform is ERα-46, which is missing the AF-1 domain and has been found to localize at the plasma membrane. It acts as a competitive inhibitor to full length ERα. A third alternatively spliced form of ERα is ERα-36, which lacks the AF-1 and AF-2 domains but has an additional 27-amino-acid sequence added at the COOH terminus. This isoform also localizes to the plasma membrane and also acts as a suppressor of full length ERα.
- Fig. 2.
A representation of the “classical” and “nonclassical” estrogen receptor signaling pathways. Estrogen receptor mediates transcription of its target genes using two types of mechanisms, these are known as “classical” and “nonclassical” signaling. First, “classical” signaling initiates with the binding of estrogen to estrogen receptor, causing it to bind directly to regions of DNA called EREs, located within transcriptional start sites of estrogen-regulated genes, which subsequently activate transcription of downstream genes. There are several mechanisms of “nonclassical” signaling. The first of these mechanisms is mediated by the signaling of growth factors (such as IGFR and EGFR) and G-protein coupled receptors, through downstream signaling molecules to estrogen receptor. These pathways mediate estrogen receptors' state of post-transcriptional modification (by affecting its phosphorylation, acetylation, methylation) and thus its activity, independent of estrogen binding. It is likely that crosstalk of these pathways not only results in estrogen-independent activation of estrogen receptor but also endocrine resistance. Signaling has also been shown to occur through truncated membrane bound forms of estrogen receptor; this signaling is usually inhibitory of full length estrogen receptor activity. Finally, another mechanism of “nonclassical” signaling requires the binding of estrogen receptor to other transcription factors (including SP-1 and AP-1), causing a recruitment of estrogen receptor to transcriptional start sites other than EREs and transcription of downstream genes.
Tables
- Table 1.
Clinical trials using drugs that target pathways known to interact with the ERα pathway in patients with ERα-positive breast disease
Drug/Combination Pathway Target(s) Patient Disease Information Phase Status PD-325901* MEK (MAPK pathway) Advanced breast cancer, colon cancer, and melanoma I-II Terminated Bevacizumab + sorafenib tosylate† RAF (MAPK pathway) Refractory, metastatic, or unresectable solid tumors I Ongoing Paclitaxel and RAD001 followed by FEC (chemotherapy)‡§ mTOR Triple negative breast tumors II Recruiting Ritonavir (preoperative)∥ Akt Newly diagnosed breast cancer patients I-II Not yet open GSK2141795¶ Akt Solid tumors/lymphomas not responsive to other therapies I Recruiting GDC-0941 + bevacizumab + paclitaxel** PI3K Locally recurrent or metastatic breast cancer Ib Recruiting BGT226§ PI3K Advanced solid malignancies including breast cancer I-II Recruiting BEZ235§ PI3K Advanced solid malignancies including breast cancer I Recruiting Temsirolimus††† mTOR Locally recurrent or metastatic breast cancer II Ongoing XL147+ XL647‡‡ PI3K Solid tumors including breast cancer I Suspended NOTE: Information from http://.ClinicalTrials.gov. Study sponsors footnoted below.
Abbreviation: mTOR, mammalian target of rapamycin.
Volume 16, Issue 10
