GATA3与乳腺癌

GATA3突变是乳腺癌的常见突变之一，出现频率大抵在第3位（第一p53，第二pik3ca）。GATA3突变目前没有专门的靶向药，替代药物也不太好找，很难应对。
很难应对也得应对，因为它并不会因为你很难应对它，它就饶过了你。
! R# D( j4 B0 V: j' X没有直接能应对的药，那就去看它影响了其他哪些通路靶点，去应对那些通路靶点；去看它影响了哪些抗癌药，用这些抗癌药的时候注意到这个问题。
( q+ n$ j( P! @4 C5 g& ~  Z总之不能束手就擒坐以待毙。对于患者和家属来说，“自学自救”的重点也就是这些一眼看上去难以应对的问题。
) N+ F' P1 \' F# p3 K% `! z6 Z
. x# n% T& \0 x5 S一、GATA3介导阿霉素耐药
$ f# f* Q, Z9 h: H8 J2 Z8 n1、《GATA3 mediates doxorubicin resistance by inhibiting CYB5R2-catalyzed iron reduction in breast cancer cells》
2、《Dysregulation of Transglutaminase type 2 through GATA3 defines aggressiveness and Doxorubicin sensitivity in breast cancer》
6 o* P; a+ o3 \% t) `3、《Clinicopathological analysis of GATA3-positive breast cancers with special reference to response to neoadjuvant chemotherapy》
" [$ \8 s( v5 i& P3 H$ o8 G& x4、《Long noncoding RNA lnc-LOC645166 promotes adriamycin resistance via NF-κB/GATA3 axis in breast cancer》

* _% m" m7 k! \) V二、gata3与mdm2在ER阳性乳腺癌中具有合成致死作用；mdm2抑制剂有靶向药apg115，化疗药伊立替康，替代药物西替利嗪等。
《GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers》
Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not yet targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth in GATA3-deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboring GATA3 somatic mutations. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

三、I3C 可治疗治疗同时表达 ERα、GATA3 和 AhR 的肿瘤；乳腺癌尤其是ER阳性乳腺癌这三者经常同时表达。
《Indole-3-carbinol triggers aryl hydrocarbon receptor-dependent estrogen receptor (ER)alpha protein degradation in breast cancer cells disrupting an ERalpha-GATA3 transcriptional cross-regulatory loop》
Estrogen receptor (ER)alpha is a critical target of therapeutic strategies to control the proliferation of hormone-dependent breast cancers. Preferred clinical options have significant adverse side effects that can lead to treatment resistance due to the persistence of active estrogen receptors. We have established the cellular mechanism by which indole-3-carbinol (I3C), a promising anticancer phytochemical from Brassica vegetables, ablates ERalpha expression, and we have uncovered a critical role for the GATA3 transcription factor in this indole-regulated cascade. I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein. I3C inhibits endogenous binding of ERalpha with the 3'-enhancer region of GATA3 and disrupts endogenous GATA3 interactions with the ERalpha promoter, leading to a loss of GATA3 and ERalpha expression. Ectopic expression of GATA3 has no effect on I3C-induced ERalpha protein degradation but does prevent I3C inhibition of ERalpha promoter activity, demonstrating the importance of GATA3 in this I3C-triggered cascade. Our preclinical results implicate I3C as a novel anticancer agent in human cancers that coexpress ERalpha, GATA3, and AhR, a combination found in a large percentage of breast cancers but not in other critical ERalpha target tissues essential to patient health.
6 u" v- s  s  Y- i5 R8 I: _
四、PARP1 在乳腺癌细胞中充当 GATA3 的转录辅激活因子， GATA3 与 PARP1 协同作用，激活 CCND1
《GATA3 cooperates with PARP1 to regulate CCND1 transcription through modulating histone H1 incorporation》
The transcription factor GATA3 is a key regulator of mammary gland development and a definitive marker of luminal breast cancer. However, the molecular mechanisms underlying the role of GATA3 in breast carcinogenesis is still not fully understood. We report here that GATA3 promotes cell proliferation and tumorigenesis by facilitating the G1/S transition through its transcription regulation of the CCND1 gene in breast cancer cells. We found that GATA3 is physically associated with poly-ADP ribose polymerase-1 (PARP1), an enzyme modifying nuclear proteins by poly(ADP-ribosyl)ation. We showed that PARP1 acts as a transcription coactivator for GATA3 in breast cancer cells and demonstrated that GATA3 cooperates with PARP1 in transactivation of the CCND1 gene. We demonstrated that PARP1 competes with linker histone H1 to maintain a transcriptional competent chromatin environment for CCND1 gene. Our results unveiled a molecular basis for the coordinated regulation between GATA3 and PARP1 in transcription activation, providing a mechanism for GATA3 in breast carcinogenesis.

五、在雌激素受体 α (ERα) 阳性乳腺癌细胞中，Aurora-A 转录受 GATA-3 正向调控，以响应雌激素。
《Estrogen-induced aurora kinase-A (AURKA) gene expression is activated by GATA-3 in estrogen receptor-positive breast cancer cells》
! J4 I& e: G* c$ o- \Aurora-A is a proto-oncogenic mitotic kinase that is frequently overexpressed in human epithelial malignancies including in breast and ovarian cancers. The mechanism of transcriptional upregulation of Aurora-A in human breast cancer is not yet elucidated. We report herein that Aurora-A transcription is positively regulated by GATA-3 in response to estrogen in estrogen receptor α (ERα)-positive cells. Transient expression of aurora-A promoter deletion mutants in luciferase constructs identified a GATA binding sequence motif as a functional regulatory element in ERα-positive breast cancer cells. Electrophoretic mobility shift assay identified the binding of regulatory proteins to the GATA element. Anti-GATA-3 antibody generated a supershifted complex. Recruitment of GATA-3 to the aurora-A promoter was verified by chromatin immunoprecipitation analysis with GATA-3 antibody. Ectopic expression of GATA-3 resulted in elevated expression of Aurora-A in both ERα-positive and negative cells while siRNA-mediated silencing led to downregulation of endogenous Aurora-A in ERα-positive cells. Estrogen treatment of ERα-positive cells induced increased Aurora-A expression with enhanced recruitment of GATA-3 to the aurora-A promoter. Finally, in the ACI rat model of estrogen-induced breast cancer, known to be associated with elevated Aurora-A expression, we observed increased expression of GATA-3 in preinvasive and invasive mammary epithelial cells exposed to prolonged estrogen treatment and in developing breast tumors. These results demonstrate a direct positive role of estrogen in regulating Aurora-A expression through activation of the ERα-GATA-3 signaling cascade and suggest that this pathway may be critical in the origin of estrogen-stimulated sporadic breast cancer.
5 s9 t- v1 n2 Y! E! I! [Aurora-A 抑制剂有Alisertib 等药物。
$ K. ^7 Z4 `; }5 k* T, I
六、基底样乳腺癌中，Gata3 的缺失使肿瘤细胞对 PARP 抑制剂 (PARPi) 敏感
  j3 f; S$ c; l8 {  U《GATA3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in breast cancer》
Background: Inadequate DNA damage repair promotes aberrant differentiation of mammary epithelial cells. Mammary luminal cell fate is mainly determined by a few transcription factors including GATA3. We previously reported that GATA3 functions downstream of BRCA1 to suppress aberrant differentiation in breast cancer. How GATA3 impacts DNA damage repair preventing aberrant cell differentiation in breast cancer remains elusive. We previously demonstrated that loss of p18, a cell cycle inhibitor, in mice induces luminal-type mammary tumors, whereas depletion of either Brca1 or Gata3 in p18 null mice leads to basal-like breast cancers (BLBCs) with activation of epithelial-mesenchymal transition (EMT). We took advantage of these mutant mice to examine the role of Gata3 as well as the interaction of Gata3 and Brca1 in DNA damage repair in mammary tumorigenesis.
Results: Depletion of Gata3, like that of Brca1, promoted DNA damage accumulation in breast cancer cells in vitro and in basal-like breast cancers in vivo. Reconstitution of Gata3 improved DNA damage repair in Brca1-deficient mammary tumorigenesis. Overexpression of GATA3 promoted homologous recombination (HR)-mediated DNA damage repair and restored HR efficiency of BRCA1-deficient cells. Depletion of Gata3 sensitized tumor cells to PARP inhibitor (PARPi), and reconstitution of Gata3 enhanced resistance of Brca1-deficient tumor cells to PARP inhibitor.
Conclusions: These results demonstrate that Gata3 functions downstream of BRCA1 to promote DNA damage repair and suppress dedifferentiation in mammary tumorigenesis and progression. Our findings suggest that PARP inhibitors are effective for the treatment of GATA3-deficient BLBCs.