New approaches to reverse resistance to hormonal therapy in human breast cancer.
Breast cancer is now the most common malignancy diagnosed in women. Growth factor and estrogen receptors elicit tight regulation of breast tumor progression. Estrogen receptors occur in about two-thirds of breast tumors, and endocrine therapy targeted to these receptors is effective in a large proportion of tumors that express both estrogen and progesterone receptors. However, after an initial period of response to hormonal therapy, such as tamoxifen, most tumors develop resistance leading to disease relapse. Emerging data suggest that previously unsuspected interactions between growth factor and estrogen signaling pathways contribute to growth promotion in breast cancer. Targeting different components of this signaling axis may allow development of more effective and less toxic anti-hormone treatments for breast cancer. In recent clinical studies, anastrozole, letrozole and exemestane, inhibitors of the estrogen synthase, aromatase, have shown advantages over tamoxifen as treatment for advanced disease. Fulvestrant is a new type of estrogen receptor antagonist that down-regulates cellular levels of estrogen receptor and has no agonist activity. Due to its unique mode of action, fulvestrant may be an ideal candidate for combination treatment with inhibitors targeted to growth factor receptor signaling pathways. New understanding of estrogen receptor genes, gene transcripts and variants, post-translational modifications of receptor protein products and interactions with other signaling networks in tumor cells are leading us to unique targeted approaches in the hormonal therapy of breast cancer.
Weinberg
Olga K
OK
Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Jonsson Comprehensive Cancer Center, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678, USA.
Marquez-Garban
Diana C
DC
Pietras
Richard J
RJ
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen