TGF‐Beta Signaling in Breast Cancer

Abstract

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.

p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-β-mediated Metastasis through Regulation of Smad2/3 Activity

“…During breast cancer progression, the tumor suppressing function of TGF-␤ is frequently subverted, thus transforming TGF-␤ from a suppressor of breast cancer formation to a promoter of its growth and metastasis (2)(3)(4). Unfortunately, how mammary tumorigenesis overcomes the cytostatic function of TGF-␤ remains incompletely understood, as does the manner in which developing breast cancers ultimately sense TGF-␤ as a pro-metastatic factor.…”

EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

“…(1,2) During breast cancer progression, transforming growth factor-b (TGF-b) levels are elevated (3,4) and the tumor-suppressing function of TGF-b is abrogated. (5) Transforming growth factor-b has at least two roles during carcinogenesis, for although it was initially found to be a tumor-suppressing cytokine, it also acts as a mediator of metastasis to the lung. (6,7) During the initial stage of metastasis, cancer cells undergo epithelial-to-mesenchymal transition (EMT), which involves loss of epithelial cell polarity, acquisition of the mesenchymal phenotype, greater motility and invasiveness, and disruption of cell-to-cell adhesion.…”

“…In the present study, the authors examined a novel small molecule inhibitor of ALK5,[3][4][5]2,4]triazolo [1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-b-induced Smad signalling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays.…”

TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival

“…The formation activates the receptor's serine/threonine kinase, which phosphorylates Smad2 or Smad3. The phosphorylated Smad2/3 forms a complex with Smad4 which moves to the nucleus and binds to DNA targets initiating complicated TGF-b effects (Dumont and Arteaga, 2000;Wakefield et al, 2001;Buck and Knabbe, 2006;Chang et al, 2007;Cox et al, 2007).…”