Molecular Changes During Breast Cancer and Mechanisms of Endocrine Therapy Resistance

Estrogen receptors (ERs) are expressed in 75% of breast cancers. ERs and their estrogen ligands play a key role in the development and progression of breast cancer. ERs have a genomic activity involving direct modulation of expression of genes vital to cell growth and survival by their classic nuclear receptors. The nongenomic activity is mediated by membrane receptor tyrosine kinases that activate signaling pathways resulting in activation of ER pathway modulators. Endocrine therapies inhibit the growth promoting activity of estrogen. ERs-positive breast cancers can exhibit de novo or acquired endocrine resistance. The mechanisms of endocrine therapy resistance are complex include deregulation of ER pathway, growth factor receptor signaling, cell cycle machinery, and tumor microenvironment. In this chapter, we will review the literature on the biology of ERs, the postulated mechanisms of endocrine therapy resistance, and their clinical implications.