Transforming growth factor-β in breast cancer: too much, too late

Abstract

The contribution of transforming growth factor (TGF)β to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGFβ as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGFβ is frequently subverted in a malignant plexus that drives breast cancer. New knowledge that TGFβ regulates the DNA damage response, which underlies cancer therapy, reveals another facet of TGFβ biology that impedes cancer control. Too much TGFβ, too late in cancer progression is the fundamental motivation for pharmaceutical inhibition. Transforming growth factor-β β in breast cancer progressionThe breadth and scope of research to define the complex roles that transforming growth factor (TGF)β plays during mammary development and breast cancer now exceeds a thousand papers. Even by the time the elegant and oftquoted study by Silberstein and Daniel in 1987 [1] put TGFβ on the mammary map as an important regulator of breast development, there was clear evidence that cancer could subvert this powerful growth inhibitory signal [2].In the past decade or so, animal tumor studies that target over-expression or inactivation of various TGFβ signaling components to different epithelial compartments have resulted in a bewildering array of conclusions due to the pleiotropic and highly context-dependent action of TGFβ on cancer suppression or progression. It is now generally agreed that during early tumor outgrowth, elevated TGFβ is tumor suppressive, whereas at later stages there is a switch towards malignant conversion and progression [3,4], as shown in neu-induced mammary tumors [5]. Inactivation of tumor suppressor genes, the sequential acquisition of oncogenic mutations, and epigenetic changes within the cancer genome divert the canonical growth inhibitory arm of the TGFβ signaling pathway towards behaviors that increase motility, invasion and metastasis (reviewed in [4]). Consistent with the response to TGFβ evolving from growth inhibition to tumor progression during advanced malignancy, the majority of breast tumors, including their metastases, are positive for nuclear phosphorylated Smad2, indicating an actively signaling TGFβ pathway [6,7].Loss of TGFβ growth inhibition and increased expression of TGFβ have been associated with malignant conversion and progression in breast, as well as gastric, endometrial, ovarian, and cervical cancers, glioma and melanoma (reviewed in [4,8]). But specific mutation of TGFβ signaling components occurs only occasionally in breast cancers. Rather, TGFβ growth response is abrogated by changes in the profile of other active signaling networks or the relative availability of transcriptional co-repressors or co-activators that bind to and modulate the canonical Smad pathway. Estrogens also appear to negatively regulate TGFβ signaling in breast cancer [9] and there is evidence that many pathway components may be epigenetically regulated during critical transitions in malignant progression [10]....

Transforming Growth Factor-β1–Mediated Activation of NF-κB Contributes to Enhanced ADAM-12 Expression in Mammary Carcinoma Cells

“…However, because of the two different types of effects of TGF-β as reported during cancer, the role of TGF-β in breast cancer still remains elusive. At early stages of the breast cancer, TGF-β is shown to inhibit epithelial cell proliferation and act as a tumor suppressor, whereas at later stages of the disease, TGF-β is shown to function as a tumor promoter (38,39). Furthermore, the action of TGF-β is shown to be dependent on the ER status of the breast cancer cells.…”

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

“…44,45 At this point, the role of TGF-β switches to a tumor promoter. It is now well accepted that during early stage of breast tumor growth, TGF-β functions as tumor suppressor, whereas at an advanced stage there is a switch of TGF-β function toward malignant progression that increases invasive phenotypes and metastasis (reviewed in 46 ). Moreover, TGF-β signaling plays an essential role in promoting self-renewal of cancer-initiating cells.…”

Construction of eukaryotic expression vector pTAR-GET- DNT?R? and its expression in breast cancer COS-7 cells

“…In the normal mammary gland, TGF-β controls tissue homeostasis by inhibiting cell cycle progression, inducing differentiation and apoptosis, and maintaining genomic integrity (Barcellos-Hoff and Akhurst, 2009). In breast cancer, higher levels of TGF-β are often detected in tumors when compared to corresponding normal mammary gland tissue, and it appears even higher in the most advanced stages of tumor progression (Gorsch et al, 1992;Tan et al, 2009).…”