Abstract
IntroductionThe re-emergence of the tumour growth factor-beta (TGF-beta)-related embryonic morphogen Nodal has recently been reported in several different human cancers. In this study, we examined the expression of Nodal in a series of benign and malignant human breast tissues to determine the clinical significance of this expression and whether Nodal could represent a potential therapeutic target in breast cancer.MethodsTissue sections from 431 therapeutically naive patients diagnosed with benign or malignant breast disease were stained for Nodal by immunohistochemistry and analysed in a blinded manner. The degree of Nodal staining was subsequently correlated with available clinical data, such as diagnoses and disease stage. These tissue findings were further explored in breast cancer cell lines MDA-MB-231 and MDA-MB-468 treated with a Nodal blocking antibody to determine biological effects for target validation.ResultsA variable degree of Nodal staining was detected in all samples. The intensity of Nodal staining was significantly greater in undifferentiated, advanced stage, invasive breast cancer compared with benign breast disease or early stage breast cancer. Treatment of human breast cancer cells in vitro with Nodal blocking antibody significantly reduced proliferation and colony-forming ability in soft agar, concomitant with increased apoptosis.ConclusionsThese data suggest a potential role for Nodal as a biomarker for disease progression and a promising target for anti-Nodal therapy in breast cancer.
Highlights
The re-emergence of the tumour growth factor-beta (TGF-beta)-related embryonic morphogen Nodal has recently been reported in several different human cancers
In cases of very strong staining (SI = 9), Nodal was detected in the surrounding stroma (Figure 1E), suggesting that Nodal may be secreted from Nodal expressing breast cancer cells
As Nodal expression is known to be regulated via a positive feedback loop during embryonic development [30], we evaluated the levels of Nodal protein in MDA-MB-231 and MDA-MB-468 cells after 72 hours of treatment with increasing concentrations of anti-Nodal antibody compared with untreated and isotype IgG treated cells
Summary
The re-emergence of the tumour growth factor-beta (TGF-beta)-related embryonic morphogen Nodal has recently been reported in several different human cancers. Data from gene expression microarrays have led to the molecular stratification of breast cancer into subgroups, such as luminal and non-luminal tumours [9]. Even with this approach, it is difficult to obtain unequivocal consensus on breast cancer classification among observers [10]. The role of the ‘CD44high/CD24low’ expression profile, proposed by some to represent a unique subpopulation of breast CSCs [12], has been challenged by others who postulate that not every breast cancer cell with this particular expression profile possesses the properties of CSCs [13] This may be due to the genetic heterogeneity within the ‘CD44high/ CD24low’ population [14], which suggests a much broader functional variability for this population. Advances in the field of CSC research have enabled us to characterize the re-emergence of specific embryonic signalling pathways in cancer cells, contributing to our understanding of the molecular mechanisms that regulate cancer cell plasticity and aggressiveness [15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
