Differential effects of overexpression of ERα and ERβ in MCF10A immortalised, non-transformed human breast epithelial cells

Abstract

This provides a model system to compare effects of oestradiol with other oestrogenic ligands in cells stably overexpressing individually ERα or ERβ.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

“…Although overexpression of ER α has been reported to result in growth inhibition by oestrogen in the ER-negative MDA-MB-231 human breast cancer cell line [76] and in MCF10A immortalized non-transformed human breast epithelial cells [77] , overexpression of ER α at lower levels in the MCF10A cells gave oestrogen-stimulated growth [75] . It is already documented that long-term oestrogen deprivation of MCF-7 human breast cancer cells results in increased levels of ER α [78] and hypersensitivity to oestrogen [79] , which can yield inhibitory growth responses to oestrogen [80] owing to a shift in dose-response [79,80] .…”

“…Studies overexpressing ER α or ER β individually in human breast cell lines lacking endogenous ER have reported apparently confl icting results on cell growth but which may also be reconciled through consideration of relative levels of ER in the cells [75] . Although overexpression of ER α has been reported to result in growth inhibition by oestrogen in the ER-negative MDA-MB-231 human breast cancer cell line [76] and in MCF10A immortalized non-transformed human breast epithelial cells [77] , overexpression of ER α at lower levels in the MCF10A cells gave oestrogen-stimulated growth [75] .…”

“…Similarly, overexpression of ER β , which is thought to be a tumour suppressor and growth inhibitor, has also been reported to give both growthinhibitory responses to oestrogen [74,81,82] and growthstimulatory responses to oestrogen [83,84] . However, in MCF10A cells, it was the clones with lower levels of overexpression of ER β that gave growth stimulation with oestrogen [75] . Although the opposing responses may result from the context of the different cell lines used or the isoform of ER β overexpressed, another explanation could also reside in a relationship between concentration of oestrogen administered Figure 4 Molecular mechanisms of oestrogen regulation of human breast cancer cell growth involve interaction of oestrogen (E)-oestrogen receptor (ER) complexes either (1) with nucleotide sequences of the ERE in the DNA (protein-DNA interaction) (see Figure 3) (direct genomic mechanism) or (2) with other transcription factors (protein-protein interaction) (indirect genomic mechanism) to infl uence levels of hundreds of mRNAs.…”

“…Brought to you by | Georgetown University Authenticated Download Date | 5/26/15 4:28 PM and level of ER expressed such that at the oestradiol concentrations used, lower levels of ER β give stimulatory effects on growth, whilst inhibitory effects occurred at the higher levels of ER β [75] .…”

How Could Endocrine Disrupters Affect Human Health?

“…For example, if an EDC acts by binding to ERs, it will not affect cells that have no ERs, but even estrogen-responsive tissues can vary in their responses to estrogen. This may, in part, relate to the relative level of the two types of ER, ERα and ERβ, which can mediate differing responses (see Chapter 3) [71]. However, it has long been known that the breast and uterus can give opposing responses to estrogen; in particular, the use of tamoxifen as an antiestrogen to inhibit ER-mediated proliferation of breast cancer cells can result in unwanted agonist responses in the uterus [72].…”