The gut microbiota in breast cancer development and treatment: The good, the bad, and the useful!

Regardless of the global progress in early diagnosis and novel therapeutic regimens, breast carcinoma poses a devastating threat, and the advances are somewhat marred by high mortality rates. Breast cancer risk prediction models based on the known risk factors are extremely useful, but a large number of breast cancers develop in women with no/low known risk. The gut microbiome exerts a profound impact on the host health and physiology and has emerged as a pivotal frontier in breast cancer pathogenesis. Progress in metagenomic analysis has enabled the identification of specific changes in the host microbial signature. In this review, we discuss the microbial and metabolomic changes associated with breast cancer initiation and metastatic progression. We summarize the bidirectional impact of various breast cancer-related therapies on gut microbiota and vice-versa. Finally, we discuss the strategies to modulate the gut microbiota toward a more favorable state that confers anticancer effects.

The anaphase-promoting complex/cyclosome co-activator, Cdh1, is a novel target of human papillomavirus 16 E7 oncoprotein in cervical oncogenesis.

The transforming properties of the high-risk human papillomavirus (HPV) E7 oncoprotein are indispensable for driving the virus life cycle and pathogenesis. Besides inactivation of the retinoblastoma family of tumor suppressors as part of its oncogenic endeavors, E7-mediated perturbations of eminent cell cycle regulators, checkpoint proteins and proto-oncogenes are considered to be the tricks of its transformative traits. However, many such critical interactions are still unknown. In the present study, we have identified the anaphase-promoting complex/cyclosome (APC) co-activator, Cdh1, as a novel interacting partner and a degradation target of E7. We found that HPV16 E7-induced inactivation of Cdh1 promoted abnormal accumulation of multiple Cdh1 substrates. Such a mode of deregulation possibly contributes to HPV-mediated cervical oncogenesis. Our mapping studies recognized the C-terminal zinc-finger motif of E7 to associate with Cdh1 and interfere with the timely degradation of FoxM1, a bona fide Cdh1 substrate and a potent oncogene. Importantly, the E7 mutant with impaired interaction with Cdh1 exhibited defects in its ability for overriding typical cell cycle transition and oncogenic transformation, thereby validating the functional and pathological significance of the E7-Cdh1 axis during cervical carcinoma progression. Altogether, the findings from our study discover a unique nexus between E7 and APC/C-Cdh1, thereby adding to our understanding of the mechanism of E7-induced carcinogenesis and provide a promising target for the management of cervical carcinoma.

Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1.

The aberrant up-regulation of the oncogenic transcription factor Forkhead box M1 (FoxM1) is associated with tumor development, progression and metastasis in a myriad of carcinomas, thus establishing it as an attractive target for anticancer drug development. FoxM1 overexpression in hepatocellular carcinoma is reflective of tumor aggressiveness and recurrence, poor prognosis and low survival in patients. In our study, we have identified the antimalarial natural product, Artemisinin, to efficiently curb FoxM1 expression and activity in hepatic cancer cells, thereby exhibiting potential anticancer efficacy. Here, we demonstrated that Artemisinin considerably mitigates FoxM1 transcriptional activity by disrupting its interaction with the promoter region of its downstream targets, thereby suppressing the expression of numerous oncogenic drivers. Augmented level of FoxM1 is implicated in drug resistance of cancer cells, including hepatic tumor cells. Notably, FoxM1 overexpression rendered HCC cells poorly responsive to Artemisinin-mediated cytotoxicity while FoxM1 depletion in resistant liver cancer cells sensitized them to Artemisinin treatment, manifested in lower proliferative and growth index, drop in invasive potential and repressed expression of EMT markers with a concomitantly increased apoptosis. Moreover, Artemisinin, when used in combination with Thiostrepton, an established FoxM1 inhibitor, markedly reduced anchorage-independent growth and displayed more pronounced death in liver cancer cells. We found this effect to be evident even in the resistant HCC cells, thereby putting forth a novel combination therapy for resistant cancer patients. Altogether, our findings provide insight into the pivotal involvement of FoxM1 in the tumor suppressive activities of Artemisinin and shed light on the potential application of Artemisinin for improved therapeutic response, especially in resistant hepatic malignancies. Considering that Artemisinin compounds are in current clinical use with favorable safety profiles, the results from our study will potentiate its utility in juxtaposition with established FoxM1 inhibitors, promoting maximal therapeutic efficacy with minimal adverse effects in liver cancer patients.

Exploring the therapeutic potential of forkhead box O for outfoxing COVID-19.

The COVID-19 pandemic has wreaked unprecedented societal havoc worldwide. The infected individuals may present mild to severe symptoms, with nearly 20% of the confirmed patients impaired with significant complications, including multi-organ failure. Acute respiratory distress imposed by SARS-CoV-2 largely results from an aggravated cytokine storm and deregulated immune response. The forkhead box O (FoxO) transcription factors are reported to play a significant role in maintaining normal cell physiology by regulating survival, apoptosis, oxidative stress, development and maturation of T and B lymphocytes, secretion of inflammatory cytokines, etc. We propose a potent anti-inflammatory approach based on activation of the FoxO as an attractive strategy against the novel coronavirus. This regime will be focused on restoring redox and inflammatory homeostasis along with repair of the damaged tissue, activation of lymphocyte effector and memory cells. Repurposing FoxO activators as a means to alleviate the inflammatory burst following SARS-CoV-2 infection can prove immensely valuable in the ongoing pandemic and provide a reliable groundwork for enriching our repertoire of antiviral modalities for any such complication in the future. Altogether, our review highlights the possible efficacy of FoxO activation as a novel arsenal for clinical management of COVID-19.

The pint- sized powerhouse: Illuminating the mighty role of the gut microbiome in improving the outcome of anti- cancer therapy.

Cancer persists as a major health catastrophe and a leading cause of widespread mortality across every nation. Research of several decades has increased our understanding of the pivotal pathways and key players of the host during tumor development and progression, which has enabled generation of precision therapeutics with improved efficacy. Despite such tremendous advancements in our combat against this fatal disease, a majority of the cancer patients suffer from poor tumor- free survival owing to the increased incidence of recurrent tumor. This is primarily due to the development of resistance against contemporary anti- cancer strategies. Recent studies have pointed towards the involvement of the human symbiotic gut microbiota in regulating the outcome of chemotherapy and immunotherapy. It does so primarily by modulating the metabolism of the drugs and host immune response, thereby enhancing the efficacy and ameliorating the toxicity. The interactions between the therapeutic agents, microbial community and host immunity may provide a new avenue for the clinical management of cancer. In addition, consumption of dietary pro-, pre- and synbiotics has been recognized to confer protection against tumor genesis and also promote improved response to traditional tumor suppressive strategies. Naturally, the use of various combinatorial regimes containing dietary supplements that improve the gut microbiome in amalgamation with conventional cancer treatment methods may significantly augment the therapeutic outcome of cancer patients and circumnavigate the resistance mechanisms that confound traditional therapies. In this review, we have summarized the role of the gut microbiome, which is the largest assembly of commensals within the human body, in regulating the efficacy and toxicity of various existing anti- cancer therapies including chemotherapy, immunotherapy and surgery. Furthermore, we have discussed how novel strategies integrating the application of probiotics, prebiotics, synbiotics and antibiotics in combination with the aforementioned anti- cancer modules manipulate the gut microbiota and, therefore, augment their therapeutic outcome. Together, such innovative anti- tumorigenic approaches may prove highly effective in improving the prognosis of cancer patients.

Significance of human microbiome in breast cancer: Tale of an invisible and an invincible.

The human microbiome is a mysterious treasure of the body playing endless important roles in the well-being of the host metabolism, digestion, and immunity. On the other hand, it actively participates in the development of a variety of pathological conditions including cancer. With the Human Microbiome Project initiative, metagenomics, and next-generation sequencing technologies in place, the last decade has witnessed immense explorations and investigations on the enigmatic association of breast cancer with the human microbiome. However, the connection between the human microbiome and breast cancer remains to be explored in greater detail. In fact, there are several emerging questions such as whether the host microbiota contributes to disease initiation, or is it a consequence of the disease is an irrevocably important question that demands a valid answer. Since the microbiome is an extremely complex community, gaps still remain on how this vital microbial organ plays a role in orchestrating breast cancer development. Nevertheless, undeniable evidence from studies has pinpointed the presence of specific microbial elements of the breast and gut to play a role in governing breast cancer. It is still unclear if an alteration in microbiome/dysbiosis leads to breast cancer or is it vice versa. Though specific microbial signatures have been detected to be associated with various breast cancer subtypes, the structure and composition of a core "healthy" microbiome is yet to be established. Probiotics seem to be a promising antidote for targeted prevention and treatment of breast cancer. Interestingly, these microbial communities can serve as potential biomarkers for prognosis, diagnosis, and treatment of breast cancer, thereby leading to the rise of a completely new era of personalized medicine. This review is a humble attempt to summarize the research findings on the human microbiome and its relation to breast cancer.

FoxM1: Repurposing an oncogene as a biomarker.

The past few decades have witnessed a tremendous progress in understanding the biology of cancer, which has led to more comprehensive approaches for global gene expression profiling and genome-wide analysis. This has helped to determine more sophisticated prognostic and predictive signature markers for the prompt diagnosis and precise screening of cancer patients. In the search for novel biomarkers, there has been increased interest in FoxM1, an extensively studied transcription factor that encompasses most of the hallmarks of malignancy. Considering the attractive potential of this multifarious oncogene, FoxM1 has emerged as an important molecule implicated in initiation, development and progression of cancer. Bolstered with the skill to maneuver the proliferation signals, FoxM1 bestows resistance to contemporary anti-cancer therapy as well. This review sheds light on the large body of literature that has accumulated in recent years that implies that FoxM1 neoplastic functions can be used as a novel predictive, prognostic and therapeutic marker for different cancers. This assessment also highlights the key features of FoxM1 that can be effectively harnessed to establish FoxM1 as a strong biomarker in diagnosis and treatment of cancer.

Tale of a multifaceted co-activator, hADA3: from embryogenesis to cancer and beyond.

Human ADA3, the evolutionarily conserved transcriptional co-activator, remains the unified part of multiple cellular functions, including regulation of nuclear receptor functions, cell proliferation, apoptosis, senescence, chromatin remodelling, genomic stability and chromosomal maintenance. The past decade has witnessed exciting findings leading to considerable expansion in research related to the biology and regulation of hADA3. Embryonic lethality in homozygous knockout Ada3 mouse signifies the importance of this gene product during early embryonic development. Moreover, the fact that it is a novel target of Human Papillomavirus E6 oncoprotein, one of the most prevalent causal agents behind cervical cancer, helps highlight some of the crucial aspects of HPV-mediated oncogenesis. These findings imply the central involvement of hADA3 in regulation of various cellular functional losses accountable for the genesis of malignancy and viral infections. Recent reports also provide evidence for post-translational modifications of hADA3 leading to its instability and contributing to the malignant phenotype of cervical cancer cells. Furthermore, its association with poor prognosis of breast cancer suggests intimate association in the pathogenesis of the disease. Here, we present the first review on hADA3 with a comprehensive outlook on the molecular and functional roles of hADA3 to provoke further interest for more elegant and intensive studies exploring assorted aspects of this protein.