RESUMEN
Endocrine therapy represents a mainstay adjuvant treatment of estrogen receptor-positive (ER+) breast cancer in clinical practice with an overall survival (OS) benefit. However, the emergence of resistance is inevitable over time and is present in one-third of the ER+ breast tumors. Several mechanisms of endocrine resistance in ER+/HER2- advanced breast cancers, through ERα itself, receptor tyrosine signaling, or cell cycle pathway, have been identified to be pivotal in endocrine therapy. The epigenetic alterations also contribute to ensuring tumor cells' escape from endocrine therapies. The strategy of combined hormone therapy with targeted pharmaceutical compounds has shown an improvement of progression-free survival or OS in clinical practice, including three different classes of drugs: CDK4/6 inhibitors, selective inhibitor of PI3Kα and mTOR inhibitors. Many therapeutic targets of cell cycle pathway and cell signaling and their combination strategies have recently entered clinical trials. This review focuses on Cyclin D-CDK4/6-RB axis, PI3K pathway and HDACs. Additionally, genomic evolution is complex in tumors exposed to hormonal therapy. We highlight the genomic alterations present in ESR1 and PIK3CA genes to elucidate adaptive mechanisms of endocrine resistance, and discuss how these mutations may inform novel combinations to improve clinical outcomes in the future.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Moduladores de los Receptores de Estrógeno/farmacología , Receptor alfa de Estrógeno/metabolismo , Receptor ErbB-2/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ciclina D/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Moduladores de los Receptores de Estrógeno/uso terapéutico , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Mutación/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor ErbB-2/genética , Transducción de Señal/efectos de los fármacosRESUMEN
The elucidation of molecular events that confer tamoxifen resistance to estrogen receptor α (ER) positive breast cancer is of major scientific and therapeutic importance. Here, we report that LEM4 overexpression renders ER+ breast cancer cells resistant to tamoxifen by activating the cyclin D-CDK4/6 axis and the ERα signaling. We show that LEM4 overexpression accelerates tumor growth. Interaction with LEM4 stabilizes CDK4 and Rb, promotes Rb phosphorylation and the G1/S phase transition. LEM4 depletion or combined tamoxifen and PD0332991 treatment significantly reverses tamoxifen resistance. Furthermore, LEM4 interacts with and stabilizes both Aurora-A and ERα, promotes Aurora-A mediated phosphorylation of ERα-Ser167, leading to increase in ERα DNA-binding and transactivation activity. Elevated levels of LEM4 correlates with poorer relapse-free survival in patients with ER+ breast cancer undergoing endocrine therapy. Thus, LEM4 represents a prognostic marker and an attractive target for breast cancer therapeutics. Functional antagonism of LEM4 could overcome tamoxifen resistance.