TGF-beta signaling in breast cancer.
The antiestrogen tamoxifen is one of the most successful drugs in the endocrine treatment of breast cancer and significantly reduces the risk of recurrence and death. Antiestrogens act by inhibiting the production of growth-stimulatory factors as well as by activating peptides with growth-inhibitory effects like transforming growth factor- beta (TGF-beta). In hormone-responsive breast cancer cells treatment with antiestrogens leads to the conversion of TGF-beta1 into a biologically active form. Expression of TGF-beta2 and TGF-beta receptor (TbetaR) II is induced via a transcriptional mechanism involving p38 MAP kinase. Inhibition of p38 abolishes antiestrogen-dependent growth inhibition. However, the role of TGF-beta in breast cancer progression is ambiguous, as it was shown to display both tumor-suppressing and -enhancing effects. A polymorphism in the promoter of TGF-beta2 that enhances expression of the protein was associated with lymph node metastasis in breast cancer patients, pointing to a role of TGF-beta2 in the process of invasion. An immunohistochemical study on TbetaRI and TbetaRII expression in breast cancer tissues indicates that the estrogen receptor (ER) status of a tumor is an important marker and a potential mediator of the transition of TGF-beta from tumor suppressor to tumor promoter. In ER-negative tumors, expression of TbetaRII was associated with a subset of tumors that appeared to be highly aggressive, leading to strongly reduced overall survival times. Further characterization of the influence of ER expression on TGF-beta signal transduction shows that ER-alpha plays a crucial role in TGF-beta signaling.
Buck
Miriam B
MB
Department of Clinical Chemistry and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Robert Bosch Hospital, Auerbachstrasse 110, 70376 Stuttgart, Germany
Knabbe
Cornelius
C
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology*
D020847:Estrogen Receptor Modulators; D016212:Transforming Growth Factor beta