Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signaling and estrogen receptor coregulators.
Estrogen receptor (ER), mediating estrogen-signaling stimuli, is a dominant regulator and a key therapeutic target in breast cancer etiology and progression. Endocrine therapy, blocking the ER pathway, is one of the most important systemic therapies in breast cancer management, but de novo and acquired resistance is still a major clinical problem. New research highlights the role of both genomic and nongenomic ER activities and their intimate molecular crosstalk with growth factor receptor and other signaling kinase pathways in endocrine resistance. These signaling pathways, when overexpressed and/or hyperactivated, can modulate both activities of ER, resulting in endocrine resistance. Thus, these signal transduction receptors and signaling molecules may serve as both predictive markers and novel therapeutic targets to circumvent endocrine resistance. Compelling experimental and clinical evidence suggest that the epidermal growth factor/HER2/neu receptor (EGFR/HER2) pathway might play a distinct role in endocrine resistance, and especially in resistance to selective estrogen receptor modulators (SERMs) such as tamoxifen. Results from preclinical studies of treatment combinations with various endocrine therapy drugs together with several potent anti-EGFR/HER2 inhibitors are very promising, and clinical trials to see whether this new strategy is effective in patients are now ongoing.
Schiff
Rachel
R
Department of Medicine, Baylor College of Medicine, Breast Center room N1230, One Baylor Plaza MS 600, Houston, TX 77030, USA. rschiff@breastcenter.tmc.edu
Massarweh
Suleiman A
SA
Shou
Jiang
J
Bharwani
Lavina
L
Arpino
Grazia
G
Rimawi
Mothaffar
M
Osborne
C Kent
CK
D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D017978:Receptors, Growth Factor