Interpreting how changes in expression of SMAD3 and SMAD4 affect their activities in the cell may distinguish their roles as a tumor suppressor or oncogene in breast cancer susceptibility. There is strong evidence for tumor suppressor func tion of SMAD3 as its loss is associated no with tumorigen esis in various cancers. However, our qPCR analysis showed that mRNA from breast cancer cases was significantly highly expressed relative to both con trol groups but was not due to the variants found in the breast cancer cases. Thus, this observation is likely attributable to regulatory factors beyond the MH2 domain. These results, together with the lack of inactivating mutations from this study and COSMIC database, strongly support that SMAD3 is not functioning as a direct tumor suppressor in breast cancer.
Nevertheless the abnormally high levels of germ line expression as well as statistically significant over expression of SMAD3 in invasive ductal carcinoma Inhibitors,Modulators,Libraries compared to normal tissues raises the possibility Inhibitors,Modulators,Libraries that epistatic interactions of SMAD3 may contribute to the oncogenic activities of TGF. SMAD3 has been shown to counteract BRCA1 dependent DNA repair in response to DNA damaging agents and over expression of SMAD3 Inhibitors,Modulators,Libraries decreases BRCA1 dependent cell survival. Therefore, it is possible that such high levels of germline SMAD3 expression may mimic a BRCA1 defi cient phenotype. Furthermore, the aberrant expression may be a mechanism that reconciles Inhibitors,Modulators,Libraries the allelic imbal ance often associated with the 15q21 locus in breast cancer with the apparent lack of SMAD3 inactivat ing mutations.
Loss of expression and allelic imbalance at the SMAD4 locus has been shown to promote carcinogenesis of gas tric, ovarian, Inhibitors,Modulators,Libraries and colorectal cancers. Overall, in our study SMAD4 cases were not differently expressed compared to controls and the variants predicted to create cryptic sites or abolish branch site did not result in aber rant expression. Interestingly, however, the breast cancer case harboring the novel c. 1350G A variant in exon 10 of SMAD4, predicted to affect ESEs, had a significant expression increase by almost five fold that was not observed in any other samples examined, indicating that the full length transcript is selleck chemicals Alisertib preferentially over produced. Increasing SMAD4 germline expression is unlikely to predispose to breast cancer due to its important role as a tumor suppressor suggesting that SMAD4 is not involved in susceptibility. However, it is appreciated that as tumori genesis develops the cell becomes increasingly desensitized to the anti proliferative effects of TGF b but remains sus ceptible to its oncogenic properties. Therefore, c.