Estrogen receptor pathways and breast cancer

Breast cancer is the most common cancer affecting women worldwide [1]. In the United States alone, an estimated 214,640 new cases of breast cancer will be diagnosed in 2006 [2]. It is estimated that one in every eight American women will be diagnosed with breast cancer within the course of her lifetime [2]. With more sensitive and accurate means of early detection and an ever-increasing number of drugs available to treat breast cancer, it is likely that women diagnosed today will live longer and may need more than one type of cancer therapy. Many cellular factors mediate breast transformation and tumor growth including growth factors, members of phosphorylation signaling cascades, oncogenes, and nuclear hormone receptors. Although each of these factors has a role in the development of breast cancer, the steroid hormone estrogen is the primary promotional factor. Epidemiologic evidence has shown that a womans overall lifetime exposure to endogenous estrogen, increased by early menarche, late menopause, and nulliparity, is the primary risk factor for developing breast cancer [3]. In 1896, George Beatson demonstrated that removal of the ovaries from a premenopausal woman with breast cancer could lead to a dramatic improvement in the course of the disease [4]. However by 1900, Stanley Boyd [5] had demonstrated, in perhaps the first clinical trial, that only one in three premenopausal women could anticipate disease control after oophorectomy. The reason for this conundrum, now known to be the selective hormonal sensitivity of breast cancer, would not be discovered until 60 years later, when Jensen and Jacobson [6] described the target-site specificity of estradiol in the immature rat. Their classic experiment showed that after an injection of [ ³H]estradiol, the radioactive steroid was bound to, and retained by, known estrogen target tissues, such as uterus, vagina, and pituitary gland. By contrast, estradiol was not retained by nontarget tissues, such as skeletal muscle. These observations led Jensen to postulate that an estrogen receptor (ER) present in estrogen target tissues must sequester the steroid specifically and initiate the cascade of biochemical events associated with estrogen action in that tissue. Increased estrogen exposure is the most important risk factor for the initiation and progression of breast cancer. Therefore, ER-α?and ERβ which mediate estrogen action, have been well studied as both predictors of hormone sensitivity in breast cancer and crucial targets for anticancer drugs.