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    • Thonzonium Bromide br Introduction Breast cancer is

    2023-01-14


    Introduction Breast cancer is the second most lethal cancer among women, accounting for approximately 40,000 deaths in the United States in 2015 [1]. The prognosis of breast cancer has improved significantly with the identification of immunohistochemical subtypes that predict response to therapy and prognosis. Thus, for each patient, there is an abundance of immunohistochemical data that can be correlated with progression or expression of other proteins in an attempt to better understand molecular pathways. Physiologically, GATA3 is a transcription factor that plays a role in the development of several tissues including the human breast, embryo, and hematopoietic tissues [2], [3], [4]. In the human breast, GATA3 expression is seen primarily in ductal epithelial Thonzonium Bromide with no staining on myoepithelial cells [5]. Consistent with its role in breast development, GATA3 knockout mice show abnormalities in nipple development [4]. Because GATA3 is strongly expressed and functional in mammary ductal epithelial cells, it is conceivable that it could play a role in carcinogenesis, which often arises from ductal epithelial cells and features ductal cells with different stages of differentiation. Thus far, GATA3 has been associated with estrogen receptor (ER) expression, progesterone receptor (PR) expression, and lower histologic grade cancer [6]. These findings support the hypothesis that GATA3 expression is reflective of a more well-differentiated status and ER positivity in breast ductal carcinomas. However, other studies paradoxically have shown that GATA3 expression does not predict response to tamoxifen [7]. Molecularly, GATA3 colocalizes with the ER enhancer, promoting ER expression, while simultaneously ER can bind to the enhancer of GATA3 [8]. This mutual enhancement is likely linked to why ER and GATA3 expression is seen to be correlated in tumors. If GATA3 expression could be correlated with another receptor besides ER and PR, it would suggest the existence of new molecular pathways, which GATA3 could interact with either directly or indirectly. Another receptor that has a well-documented role in breast development is the androgen receptor (AR). Signaling through AR is thought to account for the fact that males have less breast tissues than females in whom ER signaling predominates. Similar to AR, ER activation involves increased transcription of noncoding RNAs near ER binding sites [9], [10]. In addition, both signaling pathways are enabled by FOXA1-mediated DNA binding [11]. Similar to GATA3, AR expression is seen in a large number of triple-negative cases (25%) and is seen in approximately half of autopsy metastatic breast cancer lesions [12]. Because AR is better preserved in the metastatic setting than ER, similar to GATA3, it is possible that the 2 signaling pathways intertwine. AR has been documented to be associated with ER and PR as well as lower disease grade [13]. Among ER-positive breast cancers, AR is shown to be a positive prognosticator, and most ER-positive breast cancers are AR positive [14]. Recently, GATA3 expression has been shown to correlate with AR expression in a cohort of triple-negative breast cancers [15]. This study seeks to determine whether GATA3 expression is correlated with AR expression in all breast cancers, or whether the previous results apply strictly to the triple-negative breast cancer type. If this correlation is present, it could associate GATA3 with another large transcriptional regulatory unit. From a clinical standpoint, correlation of GATA3 with AR in breast cancer suggests that AR could be a good stain to use in the GATA3-positive tumor of unknown origin setting because metastatic carcinoma of urothelial origin rarely stains for AR [16]. This study will also explore the clinical utility of such a test.
    Materials and methods
    Results
    Discussion This study aimed to test known breast markers for correlation with GATA3 and to see if any could have utility in distinguishing GATA3+ tumors of unknown origin, which are most often of breast or urothelial origin [18].