基底样型乳腺癌与管腔型乳腺癌相比分化差,治疗手段有限。BRCA1和GATA3转录因子缺失与基底样型乳腺癌密切相关。这两者如何相互作用抑制乳腺癌尚不明确。我们前期通过建立p18缺陷小鼠管腔型乳腺癌模型发现, BRCA1或GATA3缺失均可使管腔型癌转变为基底样型癌并伴有基底/EMT转录因子的增高；BRCA1缺失引起GATA3缺乏；BRCA1缺失促进GATA3甲基化及EZH2结合到GATA3基因上。据此我们假说，在乳腺癌发生发展中存在BRCA1-GATA3轴抑制细胞向基底样分化的机制，BRCA1通过抑制DNMT和EZH2所催化的GATA3甲基化和H3K27me3以维持GATA3的转录, 而GATA3通过抑制基底/EMT转录因子而阻止细胞向基底样分化。本研究利用p18;Brca1和p18;Gata3敲除小鼠,以及肿瘤标本和细胞验证假说，探讨基底样型乳腺癌发生机理，为靶向治疗该型肿瘤提供理论依据。

Breast cancer is mainly divided into estrogen receptor (ER)-positive luminal and ER-negative basal-like tumors. Basal-like cancers are poorly differentiated, highly metastatic, with limited therapeutic approaches. Mammary epithelia are mainly composed of luminal and basal cells that are maintained by luminal and basal progenitors, respectively. The maintenance of luminal cell fate is orchestrated by networks of transcription factors (TFs), including BRCA1 and GATA3. Loss of BRCA1 or GATA3 is associated with basal-like breast cancers. How loss of BRCA1 and GATA3 leads to basal-like breast cancer remains elusive. We previously demonstrated that loss of p18INK4c (p18), a cell cycle inhibitor, leads to spontaneous development of luminal type mammary tumors in mice, and that the tumor phenotype is very similar with luminal type breast cancers in patients. It is then used as a model for investigating luminal breast cancers. We surprisingly found that deletion of either Brca1 or Gata3 in a p18 deficient background converts luminal type mammary tumors into basal-like tumors with increase of basal/EMT-TFs. Deletion of Brca1 eliminates Gata3 expression in mammary tissues and tumor cells, and reconstitution of Gata3 in Brca1-deficient tumor cells suppresses development of basal-like tumors. Deletion of Brca1 promotes methylation of GATA3 DNA and enhances EZH2 occupancy and H3K27me3 levels in the promoter of GATA3. Based on these findings, we hypothesize that there exists a BRCA1-GATA3 axis that inhibits basal-like mammary tumorigenesis, in which BRCA1 maintains GATA3 expression through suppressing DNMT-mediated DNA methylation and EZH2-mediated H3K27 histone trimethylation, whereas, GATA3 inhibits basal-like cell differentiation through suppressing basal-EMT/TFs. We propose to utilize multiple genetic mouse models, patient samples and cells to test this hypothesis. This investigation will discover novel mechanisms underlying the role of GATA3 and BRCA1 in controlling mammary cell fate and basal-like tumorigenesis. Completion of these objectives will suggest that inhibitors of DNMT and EZH2 can be used as a differentiation therapy for treatment of basal-like breast cancers.