The changing role of ER in endocrine resistance.
Estrogen receptor (ER) is expressed in approximately 70% of newly diagnosed breast tumors. Although endocrine therapy targeting ER is highly effective, intrinsic or acquired resistance is common, significantly jeopardizing treatment outcomes and minimizing overall survival. Even in the presence of endocrine resistance, a continued role of ER signaling is suggested by several lines of clinical and preclinical evidence. Indeed, inhibition or down-regulation of ER reduces tumor growth in preclinical models of acquired endocrine resistance, and many patients with recurrent ER+ breast tumors progressing on one type of ER-targeted treatment still benefit from sequential endocrine treatments that target ER by a different mechanism. New insights into the nature and biology of ER have revealed several mechanisms sustaining altered ER signaling in endocrine-resistant tumors, including deregulated growth factor receptor signaling that results in ligand-independent ER activation, unbalanced ER co-regulator activity, and genomic alterations involving the ER gene ESR1. Therefore, biopsies of recurrent lesions are needed to assess the changes in epi/genomics and signaling landscape of ER and associated pathways in order to tailor therapies to effectively overcome endocrine resistance. In addition, more completely abolishing the levels and activity of ER and its co-activators, in combination with selected signal transduction inhibitors or agents blocking the upstream or downstream targets of the ER pathway, may provide a better therapeutic strategy in combating endocrine resistance.
Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, USA.
Agostina
A
Nardone
Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, USA; Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Italy.
Carmine
C
De Angelis
Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Pharmacy Practice and Translational Research, University of Houston, College of Pharmacy, Houston, TX 77030, USA.
Meghana V
MV
Trivedi
Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, USA.
C Kent
CK
Osborne
Lester and Sue Smith Breast Center, Baylor College of Medicine, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, USA; Department of Medicine, Baylor College of Medicine, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, USA. Electronic address: rschiff@bcm.edu.
Rachel
R
Schiff
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020239:Receptor Cross-Talk; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011505:Protein-Tyrosine Kinases
Breast cancer; Co-regulators; Crosstalk; ER genomic aberrations; Endocrine resistance; Estrogen receptor