An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer

Abstract

IntroductionTransforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses.MethodsUsing a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts.ResultsTGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression.ConclusionsTumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists.

Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness

“…The results of a gene network analysis suggest that some of the phenotypic characteristics may be related to the production by IBD tumors of potent immune suppressant factors, such as TGFβ, that may alter the functional status of the immune response in the tumor microenvironment, though this hypothesis remains to be confirmed. Recent new evidence suggests that in some breast tumors, TGFβ signaling (in association with Smad3) contributes to the maintenance of an anti-proliferative effect manifesting as a reduced tumor proliferative capacity (44). Thus, the potential duality of TGFβ function, as an intrinsic tumor suppressor and potent immunosuppressive cytokine could explain, in part, the low-proliferative phenotype of IBD tumors in general, and an impaired immune response associated with IBD-FID, specifically.…”

The crossroads of breast cancer progression: insights into the modulation of major signaling pathways

“… 291 In ER + breast cancers, differing TGFβ/SMAD3-driven gene expression signatures are generated that are able to uncouple the tumor suppressive effects of TGFβ in patient cohorts with good clinical outcomes from the tumor-promoting activities of TGFβ with poorer outcomes. 292 In the near future, greater knowledge about specific gene signatures from individual tumors will be informative for the choice of therapy, such as employing TGFβ antagonists or not. The epigenetic landscape will play an increasingly important role in determining TGFβ-induced phenotypes within specific cell contexts and cancer subtypes.…”

The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ

“…Thus, the mouse model data suggests that, contrary to dogma, tumor-suppressive responses to TGFb may be retained and dominant in some instances of advanced metastatic breast cancer. We previously showed that high expression of a gene signature specifically reflecting tumor-suppressive effects of TGFb was associated with improved metastasis-free survival in clinical breast cancer cohorts (31), which supports the possibility that retention of TGFb tumor-suppressive responses may also be a feature of the human disease. In the context of ongoing clinical trials with TGFb pathway antagonists, our data suggest that good predictive biomarkers will be critical for safe and effective use of these agents, not just to identify patients who will respond therapeutically, but more importantly to eliminate those patients who are at risk for adverse on-target responses.…”

“…3C). In contrast, we previously generated a signature [TGFb/SMAD3 tumor suppressor signature score (TSTSS)] that specifically reflects just the tumor cell-autonomous suppressive effects of TGFb, and associates with good outcome in human breast cancer datasets (31). Here, we found that tumors from the StimMet response class show significantly higher expression of the TSTSS signature ( Fig.…”