Activating Estrogen Receptor Mutations in Hormone Resistant Metastatic Breast Cancer Recent advances in genome sequencing have revolutionized an era of cancer therapy where clinical and genomic information are used in assessing an individual’s risk for disease, prevention and treatment. Researchers from the University of Michigan collected normal tissue, primary diagnostic tumors and recurrent tumors from metastatic estrogen receptor α positive (ERα+) breast cancer patients that have undergone anti-estrogen and aromatase inhibitor therapy. Using DNA and RNA sequencing, several novel and acquired mutations in the ERα-ligand binding domain (LBD) were identified in tumors that survived or recurred post endocrine therapy. The ERα-LBD mutations were also found in endometrial cancers indicating a significant role of these mutations in cancer development. Testing functional activity of identified ERα mutants showed that each of the mutants had constitutive transcriptional activity that was not enhanced by estrogen. This suggests that ERα- LBD mutants can function in the absence of the ligand and maintain ER signaling. However, the transcriptional activity of each of the mutants was inhibited by the anti-estrogens suggesting that the mutations may have been acquired from aromatase inhibitor therapy. These novel ERα-LBD mutations may be used in the molecular profiling and further stratification of post endocrine therapy, recurrent breast cancer patients to identify individuals who may continue to benefit from anti-estrogen therapy. In addition, these mutations may serve as molecular targets in screening for drugs against metastatic breast cancer.
Estrogen Signaling in Breast Cancer
Breast cancer is the most common cancer diagnosed with the highest rate of cancer-related death in women worldwide. Prolonged and sustained exposure to high levels of endogenous estrogen has been a well-established underlying cause of breast cancer, and many known risk factors for breast cancer have been shown to operate via estrogen signaling pathway. Estrogens accelerate the development of breast cancer at different stages of the disease, from the mutations associated with early stages to tumor metastasis. Estrogens mediate their effects by binding to its cognate nuclear hormone receptor, the estrogen receptor (ER), which act as a ligand activated transcription factor. ER activity is regulated by the binding of ligands (endogenous estrogen or synthetic non-hormonal compounds) to the ligand binding domain (LBD). Depending on what ligand is bound, the ER can undergo several conformational changes that allows it to bind specific DNA sequences of its target genes, and to associate with other proteins to promote or suppress gene transcription. ERα (or ESR1) is the major subtype in the breast epithelium and the pro-proliferative and growth stimulatory effects of estrogen in breast cancer have been associated with the actions ERα. Approximately 70% of human breast tumors are classified as ERα+ breast cancer and blocking the estrogen signaling pathway is the mainstay therapy for breast cancer patients. Anti-estrogen therapy for breast cancer involves antagonizing the binding of estrogens to its receptor with ER antagonists such as tamoxifen and down regulating ER levels with fulvestrant. Although a large number of patients benefit from anti-estrogen therapy, 30% of ERα+ breast cancer exhibit de novo resistance while 40% acquire resistance to these therapies. In addition to anti-estrogen therapies, post-menopausal ERα+ breast cancer patients are also treated with aromatase inhibitors that block the synthesis of estrogen and effectively reduce circulating levels of estrogen. Similar to anti-estrogen therapy, patients also develop resistance to aromatase inhibitors. However, breast cancer patients that develop resistance to aromatase inhibitors, often still remain responsive to anti-estrogen therapies. Therefore, breast cancer patients can benefit from the identification of ER mutations or markers that can be used to further stratify patients based on potential to respond to anti-estrogen or aromatase inhibitor therapy.
- New marker for molecular profiling and detection of hormone resistant breast cancer
- New predictive marker for response to therapy
- Molecular target for drug screen and design for metastatic breast cancer therapy
- Improve molecular profiling of breast tumors to allow for a more personalized and effective disease management
- Guide clinicians in identifying patients who will benefit from continued anti-estrogen therapy
- Reduce burden of adverse side effects and economic cost for patients who will not benefit from ineffective therapy