A study that has uncovered core functional differences between a new oestrogen receptor could form the basis of novel and potentially more effective treatments of breast cancer as researchers sought to utilise this therapeutic target.
Oestrogen has long been linked to the development of breast cancer, both through the stimulation of breast cell growth, which can lead to mutation, and through oestrogen metabolism, which can interfere with apoptosis and DNA repair.
Oestrogen receptors act as a go-between for oestrogen activity including the metastatic growth of breast cancer cells. They are also an important marker in therapy as readable levels of oestrogen receptor proteins are expressed in a large portion of human breast cells.
US researchers think that the oestrogen receptor may play a further signalling role in other oestrogen target tissues, including uterus and prostate tissues.
By investigating the oestrogen and anti-oestrogen signalling pathways mediate by this new receptor, they could explain why some breast cancers grow worse or resistant to anti-oestrogen therapy, specifically the drug tamoxifen, which blocks oestrogen signalled responses through ER-a66 in breast tissue.
Tamoxifen is an oral selective oestrogen receptor modulator, which is used in breast cancer treatment.
Tamoxifen was invented by AstraZeneca and is sold under the brand names Nolvadex, Istubal, and Valodex. It is also available as a generic drug in a number of countries.
The study demonstrated that the new receptor, hER-?36, unlike other oestrogen receptors, is situated on the cell plasma membrane that surrounds the cell cytoplasm.
The receptor stimulates cell growth by oestrogens and anti-oestrogens through activation of the MAPK/ERK signalling pathway. This is a pathway involved in cell differentiation and growth.
According to the study, this new finding could lead to conclusion that oestrogens and anti-estrogens can both stimulate cell proliferation through membrane-associated hER-?36.
"By identifying and cloning a novel form of the human oestrogen receptor, our studies suggest that hER-?36 may have a greater potential to signal estrogen stimulated membrane responses than hER-a66," said Thomas Deuel, a >Scripps Research scientist who participated in the study.
"The results of our experiments demonstrate that the presence of hER-?36 strikingly inhibits both oestrogen-dependent and oestrogen-independent transactivation functions-which result in protein production-mediated by ER-?66," added Deuel.
Previous research conducted by the team led to the identification of the human oestrogen receptor (hER), which is mediated by specific nuclear receptors including hER-?66.
However, question marks remain over the functional significance of cell plasma membrane-initiated oestrogen signalling in human breast cancer and in other oestrogen responsive tissues that still remain unanswered.
The scientists were surprised that anti-oestrogen treatments such as tamoxifen stimulate cell growth and that the anti-oestrogens appear to have a stronger and a more prolonged activation of the MAPK/ERK signalling pathway than the oestrogens tested.
The study therefore supports the conclusion that tamoxifen functions as both agonist and antagonist of oestrogen signalling and that the expression of hER-a36 may be involved in the development of tamoxifen-resistant human breast cancer.
This raises the possibility that oestrogen-activated ER-a36 signalling initiated in the cell plasma membrane may actually accelerate the course of tamoxifen-resistant human breast cancer.
"The apparent ability of hER-?36 to trigger membrane-initiated oestrogen and anti-oestrogen signalling that leads to cell growth makes it an important new member of the oestrogen signalling pathway," Deuel said.
"Its potential to antagonise oestrogen-stimulated transactivational functions transduced by hERa66 is also an important feature of the new receptor's functional responses to estrogens. Based on our new findings, further studies of this potentially very important protein are likely to significantly advance our understanding of the diverse physiological and pathological effects of oestrogen action."