Current Cancer Drug Targets - Volume 21, Issue 10, 2021

The final stage of breast cancer involves spreading breast cancer cells to the vital organs like the brain, liver lungs and bones in the process called metastasis. Once the target organ is overtaken by the metastatic breast cancer cells, its usual function is compromised causing organ dysfunction and death. Despite the significant research on breast cancer metastasis, it’s still the main culprit of breast cancer-related deaths. Exploring the complex molecular pathways associated with the initiation and progression of breast cancer metastasis could lead to the discovery of more effective ways of treating the devastating phenomenon. The present review article highlights the recent advances to understand the complexity associated with breast cancer metastases, organotropism and therapeutic advances.

Female breast cancer recently surpassed lung cancer and became the most commonly diagnosed cancer worldwide. As per the recent data from WHO, breast cancer accounts for one out of every 8 cancer cases diagnosed among an estimated 2.3 million new cancer cases. Breast cancer is the most prevailing cancer type among women causing the highest number of cancer-related mortality. It has been estimated that in 2020, 68,5000 women died due to this disease. Breast cancers have varying degrees of molecular heterogeneity; therefore, they are divided into various molecular clinical sub types. Recent reports suggest that type 2 diabetes (one of the common chronic diseases worldwide) is linked to the higher incidence, accelerated progression, and aggressiveness of different cancers; especially breast cancer. Breast cancer is hormone-dependent in nature and has a cross-talk with metabolism. A number of antidiabetic therapies are known to exert beneficial effects on various types of cancers, including breast cancer. However, only a few reports are available on the role of incretin-based antidiabetic therapies in cancer as a whole and in breast cancer in particular. The present review sheds light on the potential of incretin based therapies on breast cancer and explores the plausible underlying mechanisms. Additionally, we have also discussed the sub types of breast cancer as well as the intricate relationship between diabetes and breast cancer.

Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in clear cell renal cell carcinoma (ccRCC) patients. However, less than half of the ccRCC patients have objective response to ICI. Objective: We aim to assess the role of DDX39B in predicting ccRCC patients'OS and ICI therapy response. Methods: DDX39B was detected by immunohistochemistry in a tissue microarray of 305 ccRCC patients. DDX39B and its relationship with the prognosis of ccRCC were also evaluated in TCGA set and a RECA-EU set. The expression of DDX39B and patients survival was also analysed in two datasets of ccRCC patients treated with ICI. Results: Overexpression of DDX39B predicted poor OS of ccRCC patients in SYSU set, TCGA set, and a RECA-EU set. DDX39B expression was significantly positive with the expression of PD-L1 and other immunomodulators., DDX39B negatively correlated with cytotoxic T-lymphocyte and HDAC10 exon 3 inclusion in ccRCC. DDX39B knockdown decreased the expression of PD-L1 and increased the expression of HDAC10 exon 3 in renal cancer ACHN cells. Patients of ccRCC with lower levels of HDAC10 exon 3 inclusion have higher TNM stage, higher Fuhrman grade and poor OS. There was a tendency that patients with DDX39B high expression had longer OS and PFS than patients with DDX39B low expression in ccRCC patients treated with ICI. Conclusion: DDX39B gene is highly expressed in ccRCC and is closely related to patients' OS. DDX39B might increase PD-L1 expression via the enhancement of HDAC10 exon 3 skipping, thereby promoting the ICI therapy response.

Background: The function of MALAT1, a long non-coding RNAs (lncRNA), in HER2- positive breast cancer remains largely unexplored. Objectives: This study aimed to investigate the effect of MALAT1 on tumor development in HER2-positive breast cancer. Methods: We detected MALAT1 expression in HER2-positive breast cancer cells and tissues, and analyzed the effects of MALAT1 on cell proliferation in HER2-positive breast cancer cells lines (BT-474 and SKBR3). A mouse xenograft model was established for detecting the function of MALAT1 in HER2-positive breast cancer. Results and Discussion: As a result, MALAT1 was remarkably up-regulated in HER2-positive breast cancer both in cells and tissues. In addition, the silencing of MALAT1 inhibited the proliferation of HER2-positive breast cancer cells both in vitro and in vivo. Furthermore, knockdown of MALAT1 by shRNA down-regulated DNMT1, DNMT3a, and DNMT3b, while up-regulated BRCA1 and PTEN in HER2-positive breast cancer both in cell lines and mouse xenograft models. Conclusion: In short, MALAT1 might be a potential biomarker and therapeutic target for HER2- positive breast cancer therapy.

Background: Glioma is the most common intracranial primary tumour of adult humans, and its pathological mechanism and molecular characteristics are still under investigation. CDK-associated cullin 1 (CACUL1) has been shown to regulate colorectal carcinoma, lung cancer, and gastric cancer development. Objective: This study aims to explore the role of CACUL1 in the pathogenesis of human glioma. Methods: CACUL1 levels in human glioma tissue microarrays were detected by immunohistochemistry analysis. Two glioblastoma cell lines, namely, U87 and U251, were transfected with CACUL1 siRNA, and cell proliferation, cell cycle, cell apoptosis, and regulating molecules, including cyclinE1, cyclinA2, CDK2, p21, Bcl2, and Bax were assessed by CCK8, flow cytometry, and Western blot. Results: CACUL1 expression in glioma tissue was significantly higher than that in normal brain tissue. CACUL1 knockdown impeded cell proliferation, induced cell apoptosis, and caused G1/S transition arrest in glioblastoma cells. The cell cycle-related proteins CDK2, cyclinE1, and cyclinA2 were dramatically decreased in the CACUL1 siRNA group compared to the non-targeting siRNA group in both U87 and U251 cells, while the CDK inhibitory protein p21 was increased in U87 cells. Additionally, the Bcl-2/Bax ratio was significantly decreased. Conclusion: CACUL1 can promote cell proliferation and suppress apoptosis of glioma cells and might serve as a potential oncogene for gliomas.

Background: Hepatocellular carcinoma (HCC) is one of the most rapidly growing solid cancers, that is characterized by hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates tumor proliferation and metastasis. It induces caveolin-1 (Cav-1) expression, a glycoprotein found on the membrane surface, then Cav-1 triggers angiogenesis and metastasis in HCC. Objective: We hypothesize that targeting HIF-1α and consequently, Cav-1 using the antioxidant natural compound such as chicoric acid and a Cav-1 inhibitor daidzein (DAZ) could be a useful approach in the management of HCC. This study was conducted to investigate the possible therapeutic efficacy of standardized chicory leaf extract (SCLE) and DAZ via modulation of HIF-1α and Cav-1 in HCC rats. Methods: Diethyl nitrosamine (DENA) was used for HCC induction. After the induction period, four groups (10 rats for each) were treated with SCLE, DAZ, a combination of both, as well as sorafenib, all compared to the non-treated control. We assessed hepatic HIF-1α protein expression, Cav-1 gene expression, serum level of AFP, hepatic tissue content of VEGF, MMP-9, oxidative stress markers MDA and SOD. Results: DAZ, SCLE, and their combination, significantly down-regulated the expression of HIF-1α, Cav-1, and consequently dampened MMP-9, VEGF, hepatic content. It has been observed that the combination treatment showed a synergistic effect compared to either treatment alone. Importantly, the combination treatment exhibited a significantly more potent effect than sorafenib. Conclusion: This study showed the potential role of the HIF-1α/Cav-1 pathway in HCC progression, moreover, SCLE and DAZ showed a potent efficacy in retarding HCC via modulation of this pathway.