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Functional and phenotypic characterizations of common syngeneic tumor cell lines as estrogen receptor positive breast cancer models

ABSTRACT: Estrogen receptor positive breast cancers (ER+ BCas) are the most common form of BCa and is increasing in incidence largely due to changes in reproductive practices in recent decades. Tamoxifen is prescribed as a component of standard of care endocrine therapy for treatment and prevention of ER+ BCa. However, it is poorly tolerated leading to low uptake of the drug in the preventative setting. Alternative therapies and preventatives for ER+ BCa are needed but development is hampered due to a paucity of syngeneic ER+ preclinical mouse models that allow pre-clinical experimentation in immunocompetent mice. Two ER positive models, J110 and SSM3, have been reported in addition to other tumor models occasionally shown to express ER (for example 4T1.2, 67NR, EO771, D2.0R and D2A1). Here we have assessed ER expression and protein levels in seven mouse mammary tumor cell lines and their corresponding tumors in addition to their cellular composition, tamoxifen sensitivity and molecular phenotype. By immunohistochemical assessment, SSM3 and to a lesser extent 67NR cells are ER+. Using flow cytometry and transcript expression we show that SSM3 cells are luminal in nature whilst D2.0R and J110 cells are stromal/basal. The remainder are also stromal/basal in nature; displaying a stromal or basal Epcam/CD49f FACS phenotype and stromal and basal gene expression signatures are overrepresented in their transcript profile. Consistent with a luminal identity for SSM3 cells, they also show sensitivity to tamoxifen in vitro and in vivo. In conclusion, the data indicates that the SSM3 syngeneic cell line is the only definitively ER+ mouse mammary tumor cell line widely available for pre-clinical research.

ORGANISM(S): Mus musculus

PROVIDER: GSE226910 | GEO | 2023/03/16

REPOSITORIES: GEO

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Project description:Breast cancer (BCa) remains the second leading cause of cancer-related mortalities in women, and acquired resistance to hormone therapies, such as tamoxifen, an estrogen receptor inhibitor, is a major hurdle in the treatment of luminal BCa. Another subtype, triple negative BCa (TNBC), is associated with aggressive disease and poor prognosis. The enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed in BCa and has been implicated in tamoxifen resistance. In addition to its PRC2-dependent canonical transcription repressive role through catalyzing histone 3 lysine 27 trimethylation (H3K27me3), evidence suggests that EZH2 can function noncanonically, in a methyltransferase-independent manner, as a transcription activator through interacting with hormone receptors and oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC), which target EZH2 and interacting proteins for degradation, can suppress both activating and repressive functions of EZH2. Previous studies have suggested that PROTACs can be leveraged to inhibit TNBC cell growth. In this study, we expand our scope to test whether EZH2 targeted PROTACs can effectively inhibit luminal BCa cell growth. We find that EZH2-targeted PROTACs, MS177 and MS8815, effectively inhibited the growth luminal BCa cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Similarly, PROTACs uniquely reduced the expression of genes involved in cell cycle progression, including forkhead box M1 (FOXM1) target genes, in BCa cell lines. Likewise, promoter regions with EZH2 binding in the absence of H3K27me3 were enriched with FOXM1 target genes in both luminal BCa and TNBC cell lines, suggesting a regulatory mechanism independent of hormone receptor status. EZH2 PROTAC treatment reduced FOXM1 protein expression and increased its degradation. In clinical samples, EZH2 mRNA expression tightly correlated with FOXM1 and FOXM1 target genes. Together, this study suggests that EZH2 targeted PROTACs represent a promising avenue of research for the future treatment of BCa, including in the setting of tamoxifen resistance.

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Functional and phenotypic characterizations of common syngeneic tumor cell lines as estrogen receptor positive breast cancer models

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