**3.2 Estrogen receptor β**

456 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

Fig. 2. Proposed cellular mechanisms mediated through the estrogen receptor. 1. Classical genomic mode of action, in which estrogen binds to an inactive ER complex, causing dissociation from heat shock and other cognate proteins, receptor dimerisation and phosphorylation (P). This can then interact directly with estrogen response elements (ERE) on target genes in concert with histone acetyl transferase (HAT) and several other coactivators (coA) or by association with the ubiquitous transcriptional factors FOS/JUN and with NCOA1 and AIB1 co-activators at API/SPI sites termed serum response element (SRE).

2. Cytoplasmically located ER can be phosphorylated by the action of AKT, SRC and

participation of PELP1.

ERK/MAPK serine/threonine kinases, downstream of signalling events initiated by various growth factors' interaction with their respective tyrosine kinase containing receptors and mediated through RAS or PI3K. This ligand- independent activated receptor can initiate transcription through the SRE. 3. Binding of estrogen to membrane–associated ER may induce assembly of complexes with either PI3K/FAK/SRC leading to activation through ERK of the transcriptional activator NCOA3 or with PELP1/SRC resulting in up-regulation of mTOR and NFKB through AKT. These mediate an action through other transcriptional response elements (TRE) on a variety of target genes without involving direct interaction of ER with chromatin. The latter mechanisms are referred to as the non-genomic pathways, that are postulated to explain those observed effects of estrogen which are too rapid to be accounted for by mechanism 1. Further 'crosstalk' between ER and RTKs may involve

It has been reported that ERß transcript levels were about 2-fold higher than those of ERα in tamoxifen-resistant as compared with tamoxifen-sensitive patients (Speirs et al., 1999) and that ERß bound to tamoxifen,raloxifen or the anti-estrogen ICI 164 384, increased transcription of AP-1-dependent genes (Paech et al., 1997). Other studies show that ERβ has a negative effect on ERα-promoted transcription (Hall & McDonnell 1999; Pettersson et al., 2000) or no correlation with response or resistance to endocrine treatment (Cappelletti et al., 2004). Development of antibodies distinguishing between the ER types and their variants has led to identification of responses in ERβ+ve but ERα-ve cancers and a potential role for the carboxy-terminally truncated variants of ERβ (ERβ2 and ERβ5) in tamoxifen responsiveness (Honma et al., 2008; Murphy and Watson, 2006). In addition to ERβ, the oestrogen-related receptor ERRγ was found to be over-expressed and mediated tamoxifen resistance in lobular invasive breast cancer models (Riggins et al., 2008).
