GATA3 is a member of the GATA transcription regulatory family and is important in directing cell fate, development, and/or differentiation in a number of cell types including luminal epithelial cells of the mammary gland [7
]. As such, there has been keen interest in the potential role of GATA3 dysregulation in the pathogenesis of breast cancer. In this study, we have used TMA technology to reassess the associations of GATA3 expression with breast cancer development and progression. Importantly, we observed a number of findings that were consistent with results from other independent cohorts therefore building on the strength of GATA3 as a beneficial biomarker for potential use clinically.
We observed that GATA3 protein expression levels were relatively higher in invasive ductal carcinoma and metatastic cells, compared to normal glandular or ductal breast epithelium. This pattern was similarly consistent in DCIS lesions compared to normal epithelium. Somewhat surprisingly, GATA3 expression levels in ductal hyperplasia were relatively elevated as well suggesting that GATA3 may not be an appropriate gauge of early detection; however, it should be noted that there were relatively few hyperplasia samples represented on the TMA, and all these lesions were in the context of women with breast cancer. On the other hand, the elevated GATA3 levels in our system may in part be a function of proliferation rather than necessarily malignant transformation.
The observed higher expression of GATA3 in hyperplastic, DCIS, and malignant lesions is interesting because it is seemingly counter to the prevailing data from in vitro
and animal studies suggesting that deletion or depletion of GATA3 in normal mammary epithelium leads to dedifferentiation and increased cell proliferation [12
]. However, a recent study by Pei, et al.
suggests that the story may not be quite so linear as they found that a normal function of GATA3 is the suppression of p18INK4C
, an inhibitor of the cell cycle [37
]. In their system, luminal A type breast malignancies which expressed higher GATA3 and lower levels of p18INK4C
, had a more favorable outcome [37
]. While this would be consistent with our observations presented here, certainly the exact function of GATA3 during malignant development and progression awaits further clarification and refinement.
While we and others have shown that GATA3 levels were generally higher in malignant cells compared to morphologically normal epithelium, within malignant tissue, relatively lower levels of GATA3 portended a poorer outcome compared to tumors with relatively higher expression. This phenomenon is shown dramatically in , where 97% of individuals with tumors expressing higher levels of GATA3 survived 10 years or more. It is important to note that these findings are consistent with and validate previous observations further emphasizing the potential relevance of GATA3 as a clinically useful biomarker [14
]. Consistent with the role of GATA3 in the development and differentiation of normal mammary epithelium, we further observed that lower levels of GATA3 were generally associated with a higher grade, less differentiated malignancy. Nevertheless, even in low grade tumors, GATA3 was a powerful predictive marker ().
GATA3 expression was correlated with expression of the estrogen receptor both in our cohort and in others [23
]. The correlation of GATA3 and ER expression levels continues to be intriguing both mechanistically and because of its potential clinical application. Despite this correlation, to date there is no compelling consensus data suggesting that ER or GATA3 directly regulate one another. Rather, the interplay between GATA3 and the ER stimulated pathways may be bridged by the forkhead family transcription factor, FOXA1 [12
]. GATA3 can potentially regulate FOXA1 expression, and in turn, FOXA1 appears to be required to promote expression of many if not all estrogen-responsive genes [12
]. Of note, our results () as well as those of Mehra et al
] show that there is not always a direct correlation between GATA3 and ER expression; within the patient population with ER+ tumors, relatively higher GATA3 expression levels remains a powerful predictor of future survival.
It is important to point out that our results confirm the findings of other groups who have used TMA or gene expression technology to investigate the prognostic value of GATA3 [19
]. While our intent when we initiated this project was not necessarily to conduct a validation study, it should be noted that the relevance and importance of independent validation is critical for identifying tangible disease biomarkers [42
]. Therefore, that GATA3 levels were predictive of outcome, as observed in multiple separate and independent patient populations, greatly strengthens its potential utility as a prognostic indicator.