Synergistic anti-cancer activity of auranofin with anti-PD-L1 therapy in triple negative breast cancer

e12583 Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.

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Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity

ACS Chemical Biology ◽

10.1021/acschembio.6b01159 ◽

2017 ◽

Vol 12 (4) ◽

pp. 1133-1140 ◽

Cited By ~ 9

Author(s):

Lindsay S. Roberts ◽

Peter Yan ◽

Leslie A. Bateman ◽

Daniel K. Nomura

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Drugs ◽

Anti Cancer

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Multifunctional unimolecular micelles loaded with the anti-cancer drug aminoflavone for triple negative breast cancer therapy

Frontiers in Bioengineering and Biotechnology ◽

10.3389/conf.fbioe.2016.01.02060 ◽

2016 ◽

Vol 4 ◽

Author(s):

Chen Guojun ◽

Brinkman Ashley ◽

Wang Yidan ◽

Hedman Curtic ◽

Havighurst Thomas ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Drug ◽

Breast Cancer Therapy ◽

Anti Cancer

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RNA-Sequencing Reveals Heat Shock 70-kDa Protein 6 (HSPA6) as a Novel Thymoquinone-Upregulated Gene That Inhibits Growth, Migration, and Invasion of Triple-Negative Breast Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.667995 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shiyi Shen ◽

Chunli Wei ◽

Junjiang Fu

Keyword(s):

Breast Cancer ◽

Rna Sequencing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Regulatory Mechanism ◽

Kegg Pathway ◽

Migration And Invasion ◽

Tnbc Cell ◽

Anti Cancer ◽

Cancer Tissues

ObjectiveBreast cancer has become the first highest incidence which surpasses lung cancer as the most commonly diagnosed cancer, and the second highest mortality among women worldwide. Thymoquinone (TQ) is a key component from black seed oil and has anti-cancer properties in a variety of tumors, including triple-negative breast cancer (TNBC).MethodsRNA-sequencing (RNA-seq) was conducted with and without TQ treatment in TNBC cell line BT-549. Gene Ontology (GO) function classification annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for these genes were conducted. Western blot and semi-quantitative RT-PCR were used to verify the regulated gene. Functional assays by overexpression or knocking down were performed for HSPA6 and its mediator TQ for inhibiting growth, migration and invasion of TNBC cells. The regulatory mechanisms and prognosis for HSPA6 for breast cancer survival were conducted through bioinformatics and online databases.ResultsAs a result, a total of 141 downregulated and 28 upregulated genes were identified and 18 differentially expressed genes, which might be related to carcinomas, were obtained. Interestingly, GO and KEGG pathway showed their roles on anti-cancer and anti-virus. Further analysis found that the HSPA6 gene was the high significantly upregulated gene, and showed to inhibit TNBC cell growth, migration and invasion. High expression of HSPA6 was positively correlated with long overall survival (OS) in patients with breast cancer, indicating the tumor-suppressive roles for HSPA6. But DNA methylation of HSPA6 may not be the regulatory mechanism for HSPA6 mRNA upregulation in breast cancer tissues, although the mRNA levels of HSPA6 were increased in these cancer tissues compared with normal tissues. Moreover, TQ enhanced the inhibitory effect of migration and invasion when HSPA6 was overexpressed; while HSPA6 was knocked down, TQ attenuated the effects of HSPA6-promoted migration and invasion, demonstrating a partially dependent manner through HSPA6 by TQ treatment.ConclusionWe have successfully identified a novel TQ-targeted gene HSPA6, which shows the inhibitory effects on growth, migration and invasion in TNBC cells. Therefore, identification of HSPA6 not only reveals a new TQ regulatory mechanism, but also provides a novel candidate gene for clinical management and treatment of breast cancer, particularly for TNBC.

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