Approximately 70% of breast cancers are estrogen receptor alpha (ERa)-positive.Drugs that target the estrogen receptor have been a mainstay of breast cancer treatment for nearly 50 years, yet many of the signaling pathways that underlie such treatments remain undiscovered or not fully explored.This especially pertains to the selective estrogen receptor modulator (SERM) tamoxifen, which remains an important agent in the treatment of ERa-positive breast cancer.Tamoxifen is the major drug used for early stage and advanced premenopausal Era positive breast cancer and for prevention of breast cancer in both younger and older women at high risk for developing the disease.Tamoxifen blocks the action of the estrogen, thereby impeding tumor cell proliferation and slowing cancer cell growth.However, there are certain subsets of patients who are not responsive to tamoxifen, either prior to or post treatment; this condition is known as tamoxifen-resistance.However, the mechanisms underlying tamoxifen-resistance are not clearly understood.A better understanding of the mechanisms underlying resistance will provide rationale for developing new therapeutic agents.