Resistance to endocrine therapy in breast cancer: molecular mechanisms and future goals

IntroductionThe majority of breast cancers (BCs) are characterized by the expression of estrogen receptor alpha (ER+). ER acts as ligand-dependent transcription factor for genes associated with cell survival, proliferation, and tumor growth. Thus, blocking the estrogen agonist effect on ER is the main strategy in the treatment of ER+ BCs. However, despite the development of targeted anti-estrogen therapies for ER+ BC, around 30-50% of early breast cancer patients will relapse. Acquired resistance to endocrine therapy is a great challenge in ER+ BC patient treatment.DiscussionAnti-estrogen resistance is a consequence of molecular changes, which allow for tumor growth irrespective of estrogen presence. Those changes may be associated with ER modifications either at the genetic, regulatory or protein level. Additionally, the activation of alternate growth pathways and/or cell survival mechanisms can lead to estrogen-independence and endocrine resistance.ConclusionThis comprehensive review summarizes molecular mechanisms associated with resistance to anti-estrogen therapy, focusing on genetic alterations, stress responses, cell survival mechanisms, and cell reprogramming.