FoxM1 regulates the expression of oestrogen receptors in breast cancer

Jul 12 2006

Research just published online in the "Journal of Biological Chemistry" identifies a new molecule involved in the regulation of oestrogen receptors (ER) expression in breast cancer.

Oestrogen is an hormone known to affect directly the survival and growth of breast cancer, and its activity is mediated through ER, which are, not only important prognostic factors in the disease, but also involved in the resistance to therapy observed in many of these tumours. The discovery, by elucidating part of the mechanism behind ER, can help to understand better breast cancer, and, in consequence, also the development of new and better therapies for the disease.

Breast cancer is still the most common malignancy among women with half a million deaths every year and one in nine of all females in the western world developing it sometime in their lives. Oestrogen is the major female sex hormone, crucial for the normal sex development and functioning of female organs and tissues, but also with a crucial role in the survival and development of many breast tumours. The hormone acts by binding to specific ER (ER-alpha and ER-beta) in a lock-and-key-mechanism that results in the activation, on the target tissue, of genes involved in cell survival and proliferation.

The role of oestrogen in cancer was first noticed about 100 years ago when researchers observed that removal of the ovaries – the major place for oestrogen production - in women with breast cancer substantially increased their chance of survival. We know now that this effect results from the fact that about 75% of human breast cancers are ER positive (mostly ER-alpha) and, as result, their grow and survival is directly dependent on oestrogen. This is also why men, that do not have ovaries and have much less oestrogen, present much lower breast cancer rates in comparison to women.

But to have ER-positive breast cancer is not only bad news since this type of tumours has the best prognosis, most probably because the hormonal therapies used in these cases (which disrupt oestrogen-ER activation) can be very effective.

Nevertheless, after an initial period of response many ER-positive tumours develop treatment resistance - even if in most of cases they maintain their oestrogen receptors - leading to disease relapses. This is believed to result from “over-activation” of ER, and consequent by-pass of the hormonal therapy effect, by growth factors, another type of hormones capable of activate ER. These cases, together with the 25% of breast tumours that are ER-negative, present a major challenge to an effective clinical management of the disease. As result it is crucial to understand the molecular and cellular mechanisms behind oestrogen receptors expression and activity for a wider and more effective breast cancer therapy.

In agreement with this idea, Patricia A. Madureira, Eric W.-F Lam and colleagues at Imperial College, London, UK and the University of Hong Kong in China looked for molecules capable of affect ER expression and/or activity, and found that transcription factor FoxM1 (transcription factors are proteins that bind to regulatory regions in the DNA leading to the expression or inhibition of specific genes) is a physiological regulator of ER-alpha expression in breast cancer cells.

Madureira, Lam and colleagues started by analysing cells from 16 different breast tumours to find that in 13 of them FoxM1 and ER-alpha expression showed a high correlation, suggesting some kind of functional link between the two molecules. Other experiments, such as the inhibition or, alternatively the introduction of FoxM1 expression in breast cancers cells, which led, respectively, to the reduction or the increase of ER-alpha levels in these cells, confirmed this role of FoxM1 in ER-alpha regulation.

These are findings that can have important therapeutic value because ER regulation/expression is, as here discussed, directly associated with the oestrogen-mediated mechanism that affects the survival and proliferation of tumour cells, and also, in the cases where hormonal therapy is being used, the control (or not) of the disease. To understand the mechanisms affecting the expression of these molecules is then fundamental to be able to have a better chance interfering and controlling breast cancer, a disease that, according to the World Health Organization, only in 2005 had more than a million of new cases diagnosed.

http://www.ox.ac.uk and http://www.imperial.ac.uk