**3. Conclusion**

Cell proliferation in normal developing breast tissue is stimulated by estrogens and estrogens may prevent osteoporosis by increasing bone mineral density (Douchi *et al.*, 2007). However, as cells can have their own set of ER splice variants that varies in time and abundance the estrogen receptor proteins can be expected to have a role in developmental regulation depending on splice variant and ligand present. ER splice variants are widely expressed in normal, premalignant and cancerous tissues and cell lines [reviewed in (Taylor *et al. 2010*)]. Co-expression of splice variants remains under investigation to understand its biological implications. Here, we briefly summarize ER expression and its role in positive or negative transcriptional activation in breast cancer.

Several studies have demonstrated that estrogens stimulate the growth of a large proportion of ERα positive breast cancers (Lazennec, 2006; Monroe *et al.*, 2005; Pedram *et al.*, 2006; Weitzmann & Pacifici, 2006). Furthermore, a decreased ERβ expression in cancer tissues as compared to benign tumours or normal tissues has been reported, whereas ERα expression seems to persist (Lazennec *et al.*, 2001, Bardin *et al.*, 2004). Recent progress in cellular experiments confirmed that ERβ opposes ERα actions in breast cancer cell lines (Sotoca *et al.*, 2011; Sotoca *et al.*, 2008; Ström *et al.*, 2004).

The main roles of ER splice variants in breast cancer development are, however, far from clear (Davies *et al.*, 2004; Saji *et al.*, 2005). ERα positivity in breast cancer in vivo is strongly associated with more favourable clinicopathological parameters. ERβ positive patients have been shown to have favourable prognosis and better survival due to better endocrinetreatment response compared with ERβ negative breast tumor patients (Davies *et al.*, 2004; Saji *et al.*, 2005).

When bound to estrogens as homodimers, each receptor activates transcription of certain target genes bearing a classical ERE in their promoter region. However, estrogen binding to ERβ can also inhibit gene transcription via AP-1 sites, while binding to ERα leads to activation. Furthermore, when heterodimers are formed, when the two receptors are coexpressed, ERβ can inhibit ERα function. Given that ER regulates cell proliferation by different mechanisms, we summarize (Table 4 and 5) by which molecular characteristics of ER this proliferation is driven.

Full activation of AF-1 in ERα induces cell proliferation in breast cancer cells (Fujita *et al.*, 2003). AF-1 activity of estrogen-ERβ is weaker compared with that of estrogen-ERα on ERE, whereas their AF-2 activities are similar (Cowley & Parker, 1999). In general ERβ has antiproliferative effects in breast cancer cells. All ERβ variants have negative effect on ERα by heterodimerization and reduce or abrogate both ligand-dependent and ligandindependent activities. Especially the ERβ2 isoform inhibits ERα-mediated estrogen action. In addition, several short ERα isoforms are able to oppose genomics actions of ERβ.

The most important point is that ERα expression induces significant cell proliferation in the absence of ERβ but not the other way around. Cell proliferation is triggered by classical genomic and non-genomic pathways. Only the wild type ERα isoform is able to induce hormone-dependent proliferation. It has been shown that most of the ER variants do not mediate ligand-dependent proliferation.

Cell proliferation in normal developing breast tissue is stimulated by estrogens and estrogens may prevent osteoporosis by increasing bone mineral density (Douchi *et al.*, 2007). However, as cells can have their own set of ER splice variants that varies in time and abundance the estrogen receptor proteins can be expected to have a role in developmental regulation depending on splice variant and ligand present. ER splice variants are widely expressed in normal, premalignant and cancerous tissues and cell lines [reviewed in (Taylor *et al. 2010*)]. Co-expression of splice variants remains under investigation to understand its biological implications. Here, we briefly summarize ER expression and its role in positive or

Several studies have demonstrated that estrogens stimulate the growth of a large proportion of ERα positive breast cancers (Lazennec, 2006; Monroe *et al.*, 2005; Pedram *et al.*, 2006; Weitzmann & Pacifici, 2006). Furthermore, a decreased ERβ expression in cancer tissues as compared to benign tumours or normal tissues has been reported, whereas ERα expression seems to persist (Lazennec *et al.*, 2001, Bardin *et al.*, 2004). Recent progress in cellular experiments confirmed that ERβ opposes ERα actions in breast cancer cell lines (Sotoca *et al.*,

The main roles of ER splice variants in breast cancer development are, however, far from clear (Davies *et al.*, 2004; Saji *et al.*, 2005). ERα positivity in breast cancer in vivo is strongly associated with more favourable clinicopathological parameters. ERβ positive patients have been shown to have favourable prognosis and better survival due to better endocrinetreatment response compared with ERβ negative breast tumor patients (Davies *et al.*, 2004;

When bound to estrogens as homodimers, each receptor activates transcription of certain target genes bearing a classical ERE in their promoter region. However, estrogen binding to ERβ can also inhibit gene transcription via AP-1 sites, while binding to ERα leads to activation. Furthermore, when heterodimers are formed, when the two receptors are coexpressed, ERβ can inhibit ERα function. Given that ER regulates cell proliferation by different mechanisms, we summarize (Table 4 and 5) by which molecular characteristics of

Full activation of AF-1 in ERα induces cell proliferation in breast cancer cells (Fujita *et al.*, 2003). AF-1 activity of estrogen-ERβ is weaker compared with that of estrogen-ERα on ERE, whereas their AF-2 activities are similar (Cowley & Parker, 1999). In general ERβ has antiproliferative effects in breast cancer cells. All ERβ variants have negative effect on ERα by heterodimerization and reduce or abrogate both ligand-dependent and ligandindependent activities. Especially the ERβ2 isoform inhibits ERα-mediated estrogen action.

The most important point is that ERα expression induces significant cell proliferation in the absence of ERβ but not the other way around. Cell proliferation is triggered by classical genomic and non-genomic pathways. Only the wild type ERα isoform is able to induce hormone-dependent proliferation. It has been shown that most of the ER variants do not

In addition, several short ERα isoforms are able to oppose genomics actions of ERβ.

**3. Conclusion** 

Saji *et al.*, 2005).

ER this proliferation is driven.

mediate ligand-dependent proliferation.

negative transcriptional activation in breast cancer.

2011; Sotoca *et al.*, 2008; Ström *et al.*, 2004).

In conclusion, the overall biological effects of E2 and other estrogenic compounds in breast cancer cells are the result of complex interplay between various mechanisms, which depend on cellular context, balance between ER subtypes, coactivators and corepressors, sequences of target EREs but also cross-talk with growth factor pathways and activity of certain kinases and phosphatases. All these factors taken together enable response to estrogens or antiestrogens.


Table 4. Summary of ERα mechanism.


Table 5. Summary of ERβ mechanism.
