GATA3 transcription factor plays an important role in the growth and differentiation of normal breast and is also closely related to the development of breast cancer, and the role of GATA3 in the development of different breast cancer subtypes varies. This paper reviews the current status of research on the relationship between GATA3 and normal breast and breast cancer development, and provides a theoretical basis for future research on the clinical application of GATA3 in breast cancer.
GATA3 is a transcription factor that regulates the genetic differentiation of a variety of cells [1, 2, 3], and as a transcription factor, GATA3 plays an important role in the development of normal breast tissues by regulating growth and promoting differentiation, and is closely related to the development of breast cancer, with different roles in different breast cancer subtypes. In this paper, we review the current status of research on the relationship between GATA3 and the development of normal breast and breast cancer.
1. Overview of GATA3 transcription factor
GATA3 belongs to the GATA family of transcription factors (GATA1 to GATA6), which bind with high affinity to the common sequence (A/T) GATA (A/G) and share a DNA-binding motif of the steroid hormone receptor superfamily C4 zinc finger structure [4], localized to chromosome 10p15 [5]. GATA1, GATA2 and GATA3 are mainly expressed in hematopoietic cells, whereas GATA4, GATA5 and GATA6 are mainly expressed in the cardiovascular system and in tissues of endodermal origin such as liver, lung and pancreas [6]. Studies have confirmed that GATA3 contributes to the normal development of a variety of tissues, such as autonomic nervous system neurons, T helper cells, hair follicle hair root endosheaths, nephropathic nephron ducts, cochlea, and mammary duct epithelial cells [1, 2, 3].
2. Relationship between GATA3 and the development of normal breast tissue
(2-1) Expression of GATA3 in normal breast tissue
Breast tissue consists of ductal epithelial tissue and stromal cells. Ductal epithelial tissue consists of a bilayer of epithelial cells (ductal epithelial cells and myoepithelial cells) that originate from a common pluripotent progenitor cell (which does not express GATA3) and differentiate individually by different pathways, similar to the TH1/TH2 system [7,8].Kouros-Mehr et al [3] found that ductal epithelial cells (or luminal cells) line the ducts, These cells are surrounded by a layer of myoepithelial/basal cells, which do not express GATA3. In addition to ductal epithelial cells, GATA3 is also expressed in white adipocyte precursors in breast tissue and in terminal end buds (TEBs) structures at puberty [9,10].
(2-2) Relationship between GATA3 and normal breast histogenesis
Prior to puberty, breast tissue is a primitive organ containing a primitive ductal epithelial network. Shortly after the onset of puberty, terminal milk bud structures develop at the tip of the mammary epithelium. The terminal milk bud consists of an outermost layer of cap cells and multiple inner layers of somatic cells, the cap cells are thought to be composed of myoepithelial progenitor cells and the somatic cells are ductal epithelial progenitor cells. The terminal milk buds proliferate, bifurcate, and invade the mammary adipose stroma in a branching-like process. In mice, this process continues for 10-12 weeks, when mature ductal branches are established and fill the fat pad [11].Kouros-Mehr et al [3] found that GATA3 is the most important transcription factor in mammary duct epithelial cells of adolescent mice and that there is expression of GATA3 in terminal mammary somatic cells, while GATA3 is not expressed in cap cells.
GATA3 is required for normal mammary gland development [3].Kouros-Mehr et al [10] showed that GATA3 is the most highly expressed transcription factor in terminal milk buds by microdot analysis of terminal milk buds.Kouros-Mehr et al [3] found that after the onset of puberty, mice knocked out of the GATA3 gene will have severe defects in mammary gland development, as evidenced by mammary tissue After 5 weeks, mammary tissues showed structural deficits, manifested by irregular luminal diameter and the absence of lateral branches, suggesting that GATA3 has a role in promoting extension and branching during mammary ductogenesis. GATA3 is a key regulator of ductal epithelial cell differentiation. Furthermore, Tong [9] et al. found that in contrast to the role of GATA3 in thymic and ductal epithelial cells, downregulation of GATA3 in white adipocyte precursors of breast tissue would lead to adipocyte differentiation, suggesting that GATA3 expression could also inhibit the continued differentiation of adipocyte precursors. Thus, GATA3 not only promotes mammary cell differentiation, mammary duct extension and branching, but also inhibits the differentiation and maturation of adipocytes in mammary tissue.
(2-3) Relationship between GATA3 and normal breast tissue development
In mature mammary tissue, GATA3 is required for the maintenance of ductal epithelial cells [3].Kouros-Mehr et al [3] found that adult mice with acute GATA3 deficiency first showed swelling of undifferentiated ductal epithelial progenitor cells accompanied by basement membrane detachment. Further analysis showed that these GATA3-deficient undifferentiated cells maintained the characteristics of ductal epithelial cells and did not transform into myoepithelial cells. However, chronic GATA3 deficiency would lead to cystein-mediated ductal epithelial cell death and insufficient lactation. This may be due to the lack of survival signals originating from the basement membrane.Asselin-Labat et al [12] found that GATA3 deficiency in mature breast tissue would result in severe cellular defects, including undifferentiated ductal epithelial cells, disorganized ducts, enhanced intercellular adhesion, and increased cell proliferation, suggesting that GATA3 maintains ductal epithelial integrity and function in mature breast tissue. adequate guidance of ductal epithelial cell differentiation is required.
How acute GATA3 deficiency in mature breast tissue leads to swelling of undifferentiated ductal epithelial progenitor cells prior to death is unclear, but this feature has been observed in the skin and lens [13,14]. These studies suggest a complex relationship between cell differentiation and the regulation of the cell growth cycle. It has been hypothesized that acute GATA3 deficiency would lead to cellular hyperinflation due to the ability of GATA3 to inhibit cell proliferation. However, GATA3 was found to inhibit the cell cycle regulatory protein inhibitor p18INK4C, which acts to inhibit cell proliferation, thus suggesting that GATA3 can promote cell proliferation [15]. Therefore, the mechanism of GATA3 in the regulation of cell differentiation and cell growth cycle needs to be clarified by further studies.
3, Relationship between GATA3 and breast cancer development
(3-1) Relationship between GATA3 and breast carcinogenesis
Yang et al [16] suggested that tumor cells selectively express regulatory factors during embryonic morphogenesis to complete epithelial-mesenchymal transition (EMT). mani et al [17] suggested that in addition to gaining kinetic energy for transformation, the acquisition of EMT-like state would lead to cells with stem cell properties . Recently, Gupta et al [18] found that certain embryonic regulatory factors can confer malignant characteristics to the cells such as invasiveness and unlimited multiplication. GATA3 is not expressed in ductal epithelial pluripotent progenitor cells, but its role is important in normal mammary gland development, suggesting that GATA3 is one of the embryonic regulators of mammary cells and thus may be associated with breast cancer development. In addition, mutations in the structural region of the GATA3 zinc finger would lead to a decrease in the ability of GATA3 to bind DNA, which is also seen in the early stages of breast carcinogenesis, suggesting an important role of GATA3 in breast carcinogenesis [19].
It was found that breast epithelial tissue consists of ductal epithelial cells (or luminal cells, which express GATA3) and myoepithelial cells (or basal cells, which do not express GATA3). Current findings suggest that the role of GATA3 may differ in the development of different molecular subtypes of breast cancer. asselin-Labat et al [12] found that GATA3 deficiency in mature breast tissue leads to severe cellular defects that cause breast cells to develop highly tumor-like characteristics, such as possessing invasive and metastatic properties. Similarly, Tlsty et al [20] suggested that loss of GATA3 function in mature breast tissue would lead to proliferation of estrogen receptor (ER)-negative breast cells lacking myoepithelial marker expression, and that GATA3 deficiency may be associated with the development of breast cancer subtypes with similar characteristics. On the other hand, Pei et al [15] found that GATA3 inhibits the transcription of the CDK repressor p18INK4c, and mice lacking INK4c spontaneously develop ER-positive ductal epithelial (luminal epithelial, luminal cell) tumors at a high ectopic rate. INK4c, a downstream regulatory target site of GATA3, inhibits the proliferation of luminal progenitor cells INK4c, as a downstream regulatory target of GATA3, inhibits the proliferation of luminal progenitor cells while suppressing the development of ductal epithelial breast cancer (or luminal breast cancer, luminal epithelial breast cancer, which refers to subtypes of breast cancer molecules that express ER and other ductal epithelial markers). In human breast cancer, INK4c low expression and GATA3 high expression are often present together in luminal-type breast cancer, but it is not clear whether GATA3 expression or overexpression can directly induce luminal-type breast cancer. In addition, Wilson et al [21] found that GATA3 is required for constituting the ERα signaling pathway and that luminal-type breast cancers are highly expressed in ERα, which also suggests that GATA3 expression may be associated with luminal-type breast carcinogenesis.
(3-2) Relationship between GATA3 and breast cancer development
The development of malignant tumors is often aggressive and metastatic in nature [22]. Kouros-Mehr et al [23] found that the expression level of GATA3 in human breast cancer cell lines was negatively correlated with their metastatic ability at the cellular level. Metastatic cell lines such as MDA-MB-231 cells had low GATA3 expression, while in contrast non-metastatic cell lines such as MCF7 cells had high GATA3 expression. In a mouse tumor implantation model, they further reintroduced GATA3 into advanced mammary tumor cells by retrovirus and found that it sufficiently induced tumor cell differentiation and significantly inhibited tumor lung metastasis. It is evident that GATA3 is closely related to the differentiation and metastasis of tumors.
Prognostic studies on breast cancer development found that low GATA3 expression was strongly correlated with indicators indicating poorer prognosis, such as high tissue grade of tumors, hypodifferentiation, positive lymph nodes, ER-negative status, and Her2/neu overexpression [24,25,26]. However, the relationship between GATA3 and breast cancer prognosis is not clear. mehra et al [25] found that GATA3 was one of the major low expressing genes in invasive carcinomas with very poor prognosis, and tumors with low GATA3 expression had significantly shorter survival than those with high expression. this was similarly confirmed by a study by Pei [15]. However, a study by Voduc et al [26] on 3119 cases of invasive breast cancer found that although GATA3 expression was a marker of better prognosis in univariate analysis, GATA3 was not an independent prognostic factor in multivariate (including patient age, tumor size, histological grade, lymph node status, ER status, Her2 status, etc.) analysis. In ER-positive patients, GATA3 was not an independent prognostic factor regardless of whether they received triamcinolone therapy. in a 10-year follow-up study, Ciocca et al [27] found no statistical difference in recurrence and survival rates between GATA3-positive and negative tumors. In contrast, GATA3 expression had a moderate prognostic value in ER-positive patients who received endocrine therapy.Jacquemier [28] et al. found that in 240 patients with ER-positive breast cancer treated with hormones, multivariate analysis showed that GATA3, VPI (vascular peritumoral invasion) , Ki67, and P53 had a statistically significant prognostic value.
4.Outlook
In summary, GATA3 plays an important role as a transcription factor in the development of normal breast tissue and breast cancer, but the role of GATA3 in the development of different subtypes of breast cancer is different. The mechanism of action of GATA3 is still unclear, but it is clear that it is highly correlated with ER expression, and the prognostic value of GATA3 in ER-positive breast cancer is a hot topic of current research. It is important to further explore the downstream gene targets of GATA3, to find the paracrine and oversecretory signals that promote GATA3 expression, and to clarify the relationship between GATA3 and breast cancer tumor cell differentiation by gene technology. Meanwhile, whether induction or inhibition of GATA3 and its downstream gene expression can be used to treat primary breast cancer or metastatic breast cancer are directions for future research.