Advanced concepts in estrogen receptor biology and breast cancer endocrine resistance : implicated role of growth factor signaling and estrogen receptor coregulators

• Published in: Cancer chemotherapy and pharmacology Vol. 56; no. S1; pp. 10 - 20
• Main Authors: SCHIFF, Rachel, MASSARWEH, Suleiman A, SHOU, Jiang, BHARWANI, Lavina, ARPINO, Grazia, RIMAWI, Mothaffar, OSBORNE, C. Kent
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.11.2005; Springer Nature B.V
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - physiopathology; Drug Resistance, Neoplasm; Estrogen Receptor Modulators - pharmacology; Female; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Pharmacology. Drug treatments; Receptors, Estrogen - drug effects; Receptors, Estrogen - physiology; Receptors, Growth Factor - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Tumors; Estrogen receptor; EGFR/HER2; Hormone therapy; Crosstalk; erbB2 Gene; Breast cancer endocrine therapy; Biology; Breast cancer; Malignant tumor; Epidermal growth factor receptor; Human Epidermal growth factor Receptor 2; Resistance; Mammary gland diseases; Signaling pathway; C-Onc gene; Advanced stage; Protooncogene; Growth factor; Hormonal receptor
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-005-0108-2

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.