Human breast cancers (HBCs) are one of the leading causes of global cancer death among women. Domesticated canines are the most affected domestic species with a prevalence rate of breast cancer more than three times in women. While the human cancer patients receive substantial diagnostic and treatment facilities, inadequacy in canine cancer care, calls for greater attention. Fine Needle Aspiration Cytology (FNAC) is comparatively simple, quick, and easily reproducible technique, which aids in pre-surgical diagnosis. In humans, FNAC has a standard protocol, the Robinson's grading system, which has high correlation with the established histological grading system of Scarff Bloom- Richardson. However, Canine Mammary Tumors (CMTs), which are known to be similar to HBCs in biological behavior and gene expressions, still bank on the histopathological methods for diagnostic purposes. This review sheds light on various factors that could be considered for developing a standard FNAC technique for CMT grading and analyzes its future perspectives.
In this perspective, we propose to leverage reactive oxygen species (ROS) induction as a potential therapeutic measure against viral infections. Our rationale for targeting RNA viral infections by pro-oxidants is routed on the mechanistic hypothesis that ROS based treatment paradigm could impair RNA integrity faster than the other macromolecules. Though antiviral drugs with antioxidant properties confer potential abilities for preventing viral entry, those with pro-oxidant properties could induce the degradation of nascent viral RNA within the host cells, as RNAs are highly prone to ROS mediated degradation than DNA/proteins. We have previously established that Plumbagin is a highly potent ROS inducer, which acts through shifting of the host redox potential. Besides, it has been reported that Plumbagin treatment has the potential for interrupting viral RNA replication within the host cells. Since the on-going Corona Virus Disease - 2019 (COVID-19) global pandemic mediated by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) exhibits high infectivity, the development of appropriate antiviral therapeutic strategies remains to be an urgent unmet race against time. Therefore, additional experimental validation is warranted to determine the appropriateness of repurposable drug candidates, possibly ROS inducers, for fighting the pandemic which could lead to saving many lives from being lost to COVID-19.
BRCA1 mutation predisposes to tumors mainly to the breast and ovaries, though the exact reason for the said tissue specificity still remains a mystery. We have shown that when breast cancer cells become defective in BRCA1, hCG is overexpressed. Also, we have demonstrated that β-hCG can promote tumor progression by inducing TGFβRII, specifically and selectively in BRCA1 defective breast cancer cells in vitro (Sengodan et al., 2017). β-hCG induces expression of hemoglobin genes and protects the cancer cells during oxidative stress, resulting in drug resistance (Sengodan et al., 2017). Since hCG has immunosuppressive action, we hypothesized that hCG might be skewing the immune response of the BRCA1 defective cells towards tumorigenesis. To examine the immunologic response of βhCG in vivo, we performed studies using NOD-SCID and Balb/C mouse models by orthotopically implanting BRCA1 wild-type, BRCA1 mutated, and βhCG overexpressed BRCA1 mutated breast cancer cells in to the fourth mammary fat pad of the mice. We used flow cytometry to characterize immune cell populations in lymphoid tissues and infiltrating the tumor. Myeloid-derived suppressor cells (MDSC), which promote tumor growth by inhibiting T-cell immunity, M1 and M2 macrophages, which are involved in antitumorigenic and protumorigenic immune responses respectively, CD4/CD8 T cells, and FoxP3 T regulatory cells, which play an important role in T cell-mediated immune response, were analyzed. Comparison of MDSC from spleen and tumor done in various studies has demonstrated that tumor MDSC have more potent suppressive activity than that from other peripheral lymphoid organs (Maenhout et al., 2013; Corzo et al., 2018). In our study there was a significant increase in the percentage of tumor MDSCs and M2 macrophages in the order, BRCA1 wild-type < BRCA1 mutant < βhCG overexpressed BRCA1 mutant breast cancers. Correspondingly, there was a significant decrease in CD8+/FOXP3+ ratio in the order, in the tumors derived from mouse models that received BRCA1 wild-type < BRCA1 mutated < βhCG overexpressed BRCA1 mutated cancers. This reflects a marked decrease in the proportion of tumor-infiltrating cytotoxic CD8+ T cells, coincident with an increase in the proportion of FOXP3+ Treg cells, which adds to the suppressive action of βhCG in BRCA1 mutated breast cancers. Collectively, these findings raise the possibility that induction of βhCG found in BRCA1-mutated tumors increases the population of MDSC and M2 macrophages, thus inhibiting the host antitumor immune response and promoting tumor growth. It was also proved for the first time in our study that βhCG causes a decrease in the proportion of cytotoxic CD8+ T cells in BRCA1 mutant cancer cells. This study shows that resistance to immunotherapy shown by BRCA1 mutated breast cancers could be reverted by modulating βhCG in BRCA1-defective cancer patients. Citation Format: Geetu Rose Varghese, Vishnu Sunil Jaikumar, Arathi Rajan, Neetha Rajan Latha, Dipyaman Patra, Priya Srinivas. βhCG regulates immune cell population in BRCA1 mutated breast cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A57.
BRCA1 mutation is reported in about 70% of all triple negative breast cancers (TNBC), while BRCA1 defect due to promoter hypermethylation is seen in about 30%–60% of sporadic breast cancers. Although PARP inhibitors and platinum‐based chemotherapy are used to treat these cancers, more efficient therapeutic approaches are required to overcome the resistance to treatment. Our previous findings have reported elevated βhCG expression but not αhCG in BRCA1 deficient breast cancers. As βhCG causes immune suppression in pregnancy, this study explored the immunomodulatory effect of βhCG in BRCA1mutated/deficient TNBC. We observed that Th1, Th2, and Th17 cytokines are upregulated in the presence of βhCG in BRCA1 defective cancers. In NOD‐SCID and syngeneic mouse models, βhCG increases the frequency of Myeloid‐derived suppressor cells in tumour tissues and contributes to macrophage reprogramming from antitumor M1 to pro‐tumour M2 phenotype. βhCG reduces the CD4+T‐cell infiltration while increasing the density of CD4+CD25+FOXP3+regulatory T‐cell in BRCA1 deficient tumour tissues. In contrast, xenograft tumours with βhCG knocked down TNBC cells did not show these immune suppressive effects. We have also shown that βhCG upregulates pro‐tumorigenic markers arginase1(Arg1), inducible nitric oxide synthase, PD‐L1/PD‐1, and NFκB in BRCA1 defective tumours. Thus, for the first time, this study proves that βhCG suppresses the host antitumor immune response and contributes to tumour progression in BRCA1 deficient tumours. This study will help develop new immunotherapeutic approaches for treating BRCA1 defective TNBC by regulating βhCG.
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