1.7 million women were diagnosed with and 521,000 women died from
breast cancer in 2012. This review considers first current treatment options: surgery;
radiotherapy; and systemic endocrine, anti-
biological, and cytotoxic
therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced
breast cancer. Next, the potential of novel drugs that target DNA repair,
growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered.
Estrogen-related receptor alpha has attracted attention as a therapeutic target in
triple-negative breast cancers with de novo resistance to, and in breast
cancers with acquired resistance to, endocrine
therapies such as
antiestrogens and
aromatase inhibitors.
Estrogen-related receptor alpha is an orphan receptor and
transcription factor. Its activity is regulated by coregulator
proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in
breast cancer cells.
Estrogen-related receptor alpha increases
breast cancer cell migration, proliferation, and
tumor development. It is expressed at high levels in
estrogen receptor-negative
tumors, and is proposed to activate
estrogen-responsive genes in endocrine-resistant
tumors. The structures and functions of the
ligand-binding domains of
estrogen receptor alpha and
estrogen-related receptor alpha, their ability to bind
estrogens,
phytoestrogens, and synthetic
ligands, and the effects of
ligand agonists, antagonists, and inverse agonists on
biological activity, are evaluated. Synthetic
ligands of
estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes,
osteoporosis, and oncology. The clinical settings in which these novel drugs might have utility in the management of advanced
breast cancer, and
biomarkers for stratification of patients likely to benefit, are discussed. Finally, the potential side effects of the novel drugs on metabolism,
osteoporosis, osteo-
metastasis, and
cachexia are considered.