Newly appreciated membrane oestrogen receptor may be important therapeutic target for breast cancer

New research at Rhode Island Hospital has uncovered the biological effects of a novel membrane oestrogen receptor, a finding that has potential implications for hormonal therapy for breast cancer. The study is published in the July edition of the journal Molecular Endocrinology.

This new study by Edward Filardo, MD, and his research team further supports earlier published work by the group that linked the transmembrane receptor, GPR30/GPER-1, to specific oestrogen binding, rapid oestrogen signalling and breast cancer metastasis. "What is exciting about this new work," says Filardo, "is that it provides some insight into the influence of GPR30 at the cellular level. It shows that oestrogen action through GPR30 allows for breast tumour cell survival, and not breast tumour cell proliferation."

Prior studies by Filardo’s group showed that oestrogen acts through GPR30 to promote the rapid release of preformed growth factors that are tethered to the surface of breast cancer cells. Their latest study was conducted in an effort to better understand the mechanism by which GPR30 triggered the release of epidermal growth factor (EGF) polypeptides from the surface of breast cancer cells.

The investigator’s found that the "growth factors" did not promote cellular growth, which by itself is not a novel finding. It has long been appreciated that EGF-related factors are also important in other cellular activities such as cellular survival. Filardo and the research team, however, found that oestrogen action through GPR30 had a more profound effect on tumour cell survival. They found that GPR30 promoted the assembly of what is called a "provisional extracellular matrix" – a crucial event in cellular survival. More specifically, they found that release of growth factor by GPR30 required the activation of a latent adhesion receptor (known as integrin a5b1).

Filardo says, "Activation of integrin a5b1 by GPR30 is a significant event because it provides a way for invading cells to gain hold once they metastasise to tissues distant to the primary breast cancer. This happens because activated integrin a5b1 can convert soluble plasma protein fibronectin into an insoluble cage. The breast cancer cells can use this to adapt to a new environment."

In general, about two-thirds of all breast cancer cases involve tumours that retain expression of oestrogen receptors (ER). They are presumed to proliferate in response to oestrogen produced by the patient. Consequently, patients with ER-positive tumours receive hormonal agents (known as ER antagonists) that act by blocking the proliferative effects of oestrogen promoted by the ER. As a result, the capacity of breast cancers to grow is reduced. The development of new drugs targeting GPR30 may be an important step in controlling breast cancer because this newly appreciated foestrogen receptor is not promoting oestrogen-dependent growth but may be critical in promoting breast tumour cell survival.

Filardo says, "There has been a recent shift toward treating ER-positive breast tumour patients with aromatase inhibitors such as tamoxifen that block oestrogen biosynthesis. The thought is that this is yet another way to prevent oestrogen from acting as its sole receptor, the ER." He concludes, "The discovery that GPR30 represents yet another oestrogen receptor with biological significance for breast cancer furthers the argument that aromatase inhibitors would effectively block oestrogen action at both types of oestrogen receptors."

(Source: Lifespan: Molecular Endocrinology: July 2009)