SOX4-mediated FBW7 transcriptional upregulation confers Tamoxifen resistance in ER+ breast cancers via GATA3 downregulation.

AIM: Tamoxifen-mediated endocrine therapy has been standard treatment for ER+ breast cancers; however, majority of them acquire resistance leading to disease relapse. Although numerous substrates of E3 ligase FBW7 are known, only a handful of factors that regulate FBW7 expression and function are reported. In particular, there remains a lack of in-depth understanding of FBW7 transcriptional regulation. MATERIALS AND METHODS: Luciferase reporter assay was performed after cloning full length and truncated FBW7 promoters followed by Chromatin immunoprecipitation assay to validate binding of SOX4 on FBW7 promoter. Transcriptional regulation of FBW7 by SOX4 and their biological consequences with respect to ER+ breast cancer was then evaluated using immunoblotting and other cell based assays. KEY FINDINGS: SOX4 positively regulates FBW7 at transcriptional level by binding to three putative SOX4 biding sites within 3.1 kb long FBW7 promoter. Analysis of publicly available RNAseq datasets also showed a positive correlation between SOX4 and FBW7 mRNA in cancer cell lines and patient samples. qPCR and Immunoblotting confirmed that transiently or stably expressed SOX4 induced both endogenous FBW7 mRNA and protein levels. Our findings further demonstrated that increased levels of SOX4 and FBW7 in MCF7 mammospheres promoted cancer stemness and tumor cell dormancy. We further showed that both MCF7 mammospheres and MCFTAMR cells had elevated SOX4 levels which apparently enhanced FBW7 to potentiate GATA3 degradation leading to enhanced stemness, tumor dormancy and Tamoxifen resistance in MCF7TAMR as well as patients with ER+ breast cancers. SIGNIFICANCE: Targeting SOX4-FBW7-GATA3 axis may overcome tamoxifen resistance in ER+ breast cancers.

Synergistic antitumor activity of 5-fluorouracil and atosiban against microsatellite stable colorectal cancer through restoring GATA3.

Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban, an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo. Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu.

A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T-cell lymphomas.

The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.

Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.

The transcription factor Gata-3 is a defining marker of the 'luminal' subtypes of breast cancer. To gain insight into the role of Gata-3 in breast epithelial development and oncogenesis, we have explored its normal function within the mammary gland by conditionally deleting Gata-3 at different stages of development. We report that Gata-3 has essential roles in the morphogenesis of the mammary gland in both the embryo and adult. Through the discovery of a novel marker (beta3-integrin) of luminal progenitor cells and their purification, we demonstrate that Gata-3 deficiency leads to an expansion of luminal progenitors and a concomitant block in differentiation. Remarkably, introduction of Gata-3 into a stem cell-enriched population induced maturation along the alveolar luminal lineage. These studies provide evidence for the existence of an epithelial hierarchy within the mammary gland and establish Gata-3 as a critical regulator of luminal differentiation.