Turn in Breast Cancer Care: Upregulation of Estrogen Signal May Be Much More Effective than Its Inhibition

Although our understanding of breast cancer development has been shown a remarkable increase in the past 50 years, the disease is a serious public health problem and poses major challenges even today. In 1896, estrogen withdrawal by oophorectomy resulted in a transient tumor regression in the minority of premenopausal breast cancer cases. From that time onward, a direct correlation between serum estrogen concentration and tumor growth has been erroneously supposed and estrogen withdrawal gained great popularity among specialists of breast cancer care. Development of chemically modified synthetic estrogens and progestins and their use in menopausal hormone therapy (MHT) resulted in controversial risks and benefits concerning women’s health and further supported the belief of estrogen-induced breast cancer. The ambiguous correlations between MHT and breast cancer risk revealed that synthetic hormones are not bioidentical, but rather they are endocrine disruptors deregulating the work of genomic machinery. Identification of estrogen receptors (ERs) as transcription factors in targeted tissues was a milestone in cancer research promoting immense development in human genetics and in understanding the regulation of the whole genomic machinery. Estrogen activation of ERs was mistakenly regarded as a fuel for breast cancer initiation and growth, and an increased ER positivity in tumors was erroneously evaluated as aggressive survival technique. By contrast, elevated ER expression of tumors showed direct correlation with high differentiation and good prognosis of the disease. In addition, the overexpression of human epidermal growth factor receptor (HER-2) in breast tumors is erroneously regarded as a direct activator of cell proliferation. Conversely, in tumors, growth factor receptors serve the regulation of ERs via unliganded pathway helping DNA restoration and apoptotic death. Breast cancer cells need medical help for their self-directed upregulation of estrogen signal and DNA repair rather than further deterioration of their genomic mechanisms. The principle of estrogen-induced breast cancer led to the introduction of antiestrogen therapies against this tumor and inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. Later, near all patients showing earlier good tumor responses experienced secondary resistance to endocrine therapy leading to metastatic disease and fatal outcome. Molecular events in tumors, responsive and unresponsive to antiestrogen therapy, illuminated that a successful inhibition of liganded ER activation stimulates, while a strong compensatory upregulation of estrogen signal inhibits the growth of tumor and helps patient’s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition, and DNA repair reveals that estrogen treatment and upregulation of ER expression may bring about a great turn in breast cancer care.