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    • As an internal control this study validated many of

    2023-04-13

    As an internal control, this study validated many of the known associations between GATA3 and predictive markers. GATA3 was shown to be associated with ER and PR, which are both well-known correlations. GATA3 was also negatively correlated with nuclear grade, which is consistent with our knowledge of GATA3 as a marker of better differentiation. Both ER and PR were negatively correlated with nuclear grade, reflecting a similar process. HER2 was positively correlated with size and nuclear grade, supporting what is known of HER2: that it is a negative prognosticator. Lastly, nuclear grade was positively correlated with size, showing that tumors that are larger at the time of diagnosis are often of a higher nuclear grade and more aggressive. GATA3 staining frequencies have been well reported in ductal carcinomas but not as well documented in lobular and mucinous carcinomas. In this study, 8 of 9 lobular carcinomas stained for GATA3, and all mucinous carcinomas stained for GATA3. A previous study showed that 87% of lobular carcinomas show androgen receptor expression, and this study validated those results with 8 of 9 (89%) showing strong AR expression [19]. Along with the known correlations, this study revealed a previously undocumented correlation between GATA3 and AR (r=0.61; 95% CI 0.52-0.68) that was considerably stronger than that between either GATA3 and ER (r=0.46; 95% CI 0.36-0.55) or GATA3 and PR (r=0.38). A total of 199 of 259 (77%) cases were positive for ER, AR, and GATA3, and one such case is depicted in Fig. 5. This suggests that as well as modulating ER expression by binding to its enhancer, GATA3 could also bind an AR enhancer or influence the AR regulatory network in some way. If verified, this would represent a new signaling functionality for GATA3. Simultaneously, ER is known to regulate GATA3 expression, so the GATA3 gene could have an enhancer 7915 receptor that is bound by AR as well. Alternatively, GATA3 along with AR could both be playing a reactive role; AR has been known to be a positive prognosticator in ER-positive tumors because it has an antioncogenic role, countering the effect of ER overexpression. Studies have shown AR signaling to have a buffering effect on ER-mediated c-myc oncogenic activity [20]. Experiments in monkeys have shown that testosterone has antagonistic effects on ER signaling [21]. Cell line studies have shown an inhibitory effect of AR on ER signaling. Breast cancer cell line GATA3 overexpression is associated with less metastases in a nude mouse model [22]. Because GATA3 is more closely correlated with AR than ER, there is a possibility that it too has an antioncogenic effect, regulating ER-mediated c-myc signaling. This heightened correlation of AR with GATA3 over ER with GATA3 could also reflect the fact that AR marks ER-positive breast cancers most likely in a buffering capacity and that it marks molecular apocrine AR-positive triple-negative breast cancers; both groups are likely to be GATA3 positive, but only the former would be ER positive. The correlation of GATA3 and AR by histologic subtype revealed that lobular carcinomas and ductal carcinomas with lobular features both showed very strong correlations between GATA3 and AR expression. In lobular carcinoma, this correlation was perfect (r=1), with 8 of 9 cases showing strong GATA3 expression (score 2) and those same cases showing strong AR expression as well (score 2). The 1 case with no GATA3 expression also showed no AR expression. In ductal carcinoma with lobular features, every case of 16 that showed GATA3 expression also showed AR expression, whereas every case that was negative for GATA3 was also negative for AR, for a perfect correlation coefficient of 1 if only the presence of staining is considered, not degree of staining. This very high correlation was not seen in the pure ductal carcinoma group (r=0.62 if both weak staining and strong staining are considered, and r=0.6 if the 2 scores are grouped into 1 category) (Fig. 6). This finding suggests that whatever pathway links GATA3 and AR signaling, it most likely plays a more active role in tumors with lobular differentiation than ductal carcinomas. Mucinous carcinomas showed no statistically significant correlation between GATA3 and AR, suggesting that, in these tumor types, the linking pathway may be irrelevant.