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Review
. 2022 Sep:237:108253.
doi: 10.1016/j.pharmthera.2022.108253. Epub 2022 Jul 21.

Triple negative breast cancer (TNBC): Non-genetic tumor heterogeneity and immune microenvironment: Emerging treatment options

Jae Young So  1 , Joyce Ohm  2 , Stan Lipkowitz  3 , Li Yang  4
Affiliations
Review

Triple negative breast cancer (TNBC): Non-genetic tumor heterogeneity and immune microenvironment: Emerging treatment options

Jae Young So et al. Pharmacol Ther. 2022 Sep.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intra-tumoral heterogeneity, and frequently develops resistance to therapies. Tumor heterogeneity and lack of biomarkers are thought to be some of the most difficult challenges driving therapeutic resistance and relapse. This review will summarize current therapy for TNBC, studies in treatment resistance and relapse, including data from recent single cell sequencing. We will discuss changes in both the transcriptome and epigenome of TNBC, and we will review mechanisms regulating the immune microenvironment. Lastly, we will provide new perspective in patient stratification, and treatment options targeting transcriptome dysregulation and the immune microenvironment of TNBC patients.

Keywords: Epigenetic; Immune; Immune checkpoint blockade; TNBC; Therapy-resistance; Transcriptome; Tumor microenvironment.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that there are no conflicts of interest.

Figures

Figure 1.
Figure 1.. Immune checkpoint blockade (ICB).
The blockade of immune check point inhibitors takes the advantage of specific ligand-receptor interaction such as PDL1-PD1. The immune checkpoint inhibitory receptors and ligands are indicated in T cells and cancer cells. PD1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; LAG3: lymphocyte activating 3; TCR: T-cell receptor; MHC: major histocompatibility complex; CD: cluster of differentiation; CTLA4: cytotoxic T-lymphocyte associated protein 4.
Figure 2.
Figure 2.. Epigenetic drugs (Epi-drugs) and their targets.
Inhibitors of DNA methyltransferases (DNMT1, 3A and 3B) targeting DNA methylation; inhibitors of histone writers (histone acetyltransferases or HATs), histone erasers (histone deacetylases or HDACs) and histone readers (bromodomain proteins or BRDs) targeting histone modification; Inhibitors of PRC2 subunits (EZH2 and EED) targeting enzymatic activity and H3K27me3 binding pocket for chromatin remodeling. BET: bromodomain and extra-terminal protein; GCN5: general control non-repressed 5 protein; PCAF: P300/CBP-associated factor; MYST: HAT family of MOZ, Ybf2, Sas2 and Tip60; SIRT: Sirtuin; BRDT: bromodomain testis associated; PRC2: polycomb repressive complex 2; EZH2: enhancer of zeste homolog 2; EED: embryonic ectoderm development.
Figure 3.
Figure 3.. Inhibitors modulating the immune microenvironment.
Inhibitors targeting the interaction of cytokine/chemokine and their receptors in inflammatory monocytes, macrophages, neutrophils, as well as tumor cells. CSF1: colony stimulating factor 1; CSF1R: colony stimulating factor 1 receptor; CXCL1/5: C-X-C motif ligand 1 and 5; CXCR2: CXC chemokine receptor 2; CCL2: C-C motif chemokine ligand 2; CCR2: C-C motif chemokine receptor 2.
See this image and copyright information in PMC

References

    1. Sharma P. Biology and Management of Patients With Triple-Negative Breast Cancer. Oncologist 2016;21(9):1050–62 doi 10.1634/theoncologist.2016-0067. - DOI - PMC - PubMed
    1. Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. J Clin Oncol 2017;35(10):1049–60 doi 10.1200/JCO.2015.63.1010. - DOI - PMC - PubMed
    1. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376(22):2147–59 doi 10.1056/NEJMoa1612645. - DOI - PubMed
    1. Huo X, Li J, Zhao F, Ren D, Ahmad R, Yuan X, et al. The role of capecitabine-based neoadjuvant and adjuvant chemotherapy in early-stage triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer 2021;21(1):78 doi 10.1186/s12885-021-07791-y. - DOI - PMC - PubMed
    1. Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, et al. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol 2022;40(10):1051–8 doi 10.1200/JCO.21.02054. - DOI - PMC - PubMed

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