The Importance of ERα/ERβ Ratio in Breast Cancer: Mitochondrial Function and Oxidative Stress

Abstract

Breast cancer is the most commonly diagnosed malignancy within the female population of developed countries and is the first leading cause of cancer deaths in women. In the European Union (EU27) every year there are an estimated 319.000 new cases diagnosed, and approximately 131.000 deaths, which comprises 16.7% of all cancer caused deaths in women (Ferlay et al., 2007). The causes of breast cancer are not fully understood, but the epidemiology of the disease clearly shows that hormonal factors play a key role. Estrogen production appears as one potential risk factor among women worldwide because it stimulates the proliferation of breast epithelial cells (Ekbom et al., 1997; Ferlay et al., 2007). Coincident with this proliferation, breast cancer risk increases in early menarche, late menopause and with obesity in postmenopausal women (situations where there is a direct association between estrogen and breast cancer risk). In general, breast cancer risk decreases around 5% with each year that menarche is delayed. Breast cancer incidence rates also increase more slowly after menopause; therefore a woman with a natural menopause at age 45 years has half the risk of developing this type of cancer that a woman with menopause at age 55 (Kelsey et al., 1993; Key et al., 2001). Childbearing seems to have a dual effect on risk of breast cancer (Key et al., 2001). On one hand the immediate effect is to temporarily increase the risk after a birth, yet on the other, this risk diminishes in the long term and the overall effect of a pregnancy is to reduce the overall risk of developing this disease. It appears that the negative short term effect is due to the increase in estradiol levels in early pregnancy. However, has been seen that premenopausal parous women have lower global levels of circulating estradiol than in nulliparous premenopausal women. This effect is observed among postmenopausal women, suggesting that this diminution is stable (Ewertz et al., 1990). Women who have had at least one child have around a 25% reduction in breast cancer risk compared to nulliparous women (Layde et al., 1989; Ewertz et al., 1990). Moreover, the use of menopausal hormonal therapy increases the risk of breast cancer; in fact, the use of these estrogen preparations over a period of 10 years, increases cancer risk by 35%(Key et al., 2001). Other risk factor associated with breast cancer is family history and genetic predisposition. Women with a first-degree relative have about a two-fold risk of