An ESR1 gene mutation, which encodes for the estrogen receptor (ER) protein, is one of the potential mechanisms of therapy resistance. The ESR1 mutations result in conformational changes in the ER leading to subsequent estrogen-independent transcriptional activity. The mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Estrogen receptor alpha (ERalpha) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERalpha is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERalpha in breast cancer patients indicates invasiveness and poor prognosis. ESR1 as a direct target of miR-31a-3p and suggest that miR-31a-3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer. Polymorphisms of the estrogen receptor gene alpha (ESR1) are consistently been associated with bone mineral density (BMD) and fracture.