Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine-derived phytochemicals curcumin, resveratrol, and berberine Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy In addition, the impact of TCM treatment on DNA methylation, histone modification, and the regulation of noncoding RNAs is discussed Furthermore, we have highlighted studies of TCM therapy that modulate the tumor microenvironment and eliminate cancer stem cells The information compiled in this review will serve as a solid foundation to formulate hypotheses for future studies on TCM-based cancer therapy

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.2108

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science.

The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) are caused by invasion and metastasis. The EMT plays an important role in invasion and subsequent metastasis. Several distinct biological events integrate a cascade that leads not only to a change from an epithelial to mesenchymal phenotype, but allows for detachment, migration, invasion and ultimately, colonization of a second site. Understanding the biological intricacies of the EMT may provide important insights that lead to the development of therapeutic targets in pre-invasive and invasive breast cancer, and could be used as biomarkers identifying tumor subsets with greater chances of recurrence, metastasis and therapeutic resistance leading to death.

https://www.mdpi.com/2077-0383/5/7/65/pdf

EMT in Breast Carcinoma-A Review.

Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein's anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors.

https://www.mdpi.com/1422-0067/17/10/1681/pdf

The Fascinating Effects of Baicalein on Cancer: A Review

Multidrug resistance (MDR) resulting from different defensive mechanisms in cancer is one of the major obstacles of clinical treatment. To circumvent MDR many reversal agents have been developed, but most of them fail in clinical trials due to severely adverse effects. Recently, certain natural products have been reported to overcome MDR, including flavonoids which are abundant in plants, foods, and herbs. The structure of flavonoids can be abbreviated as C6-C3-C6 (C for carbon), and further categorized into flavonoids, iso-flavonoids and neo-flavonoids, according to their structural backbones. Flavonoids possess multiple bioactivities, and a growing body of research has indicated that both flavonoids and iso-flavonoids can either kill or re-sensitize conventional chemotherapeutics to resistant cancer cells. Here, we summarize the research and discuss the underlying mechanisms, concluding that these flavonoids do not function as specific regulators of target proteins, but rather as multi-functional agents that negatively regulate the key factors contributing to MDR.

/pdf/reversal-of-multidrug-resistance-in-cancer-by-multi-1erp585xk1.pdf

Reversal of Multidrug Resistance in Cancer by Multi-Functional Flavonoids.

Purpose Baicalein, a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. However, little is known about the underlying mechanism in human breast cancer cells. In this study, we examined the apoptotic and autophagic pathways activated following baicalein treatment in human breast cancer cells in vitro and in vivo. Materials and methods In in vitro study, we used MTT and clone formation assay to confirm the inhibitory role of baicalein on proliferation of MCF-7 and MDA-MB-231 breast cancer cells. Apoptosis was detected employing Hoechst 33258 staining, JC-1 staining, and flow cytometry. Autophagy was monitored by acridine orange staining and transmission electron microscopy observation. Quantitative real-time PCR and Western blot analysis were employed to study the effects of baicalein on PI3K/AKT signaling components of MCF-7 and MDA-MB-231 breast cancer cells. In in vivo study, the effect of baicalein was tested with a breast cancer cells transplantation tumor model. Results Our study showed that baicalein has the potential to suppress cell proliferation, induce apoptosis and autophagy of breast cancer cells in vitro and in vivo. Furthermore, baicalein significantly downregulated the expression of p-AKT, p-mTOR, NF-κB, and p-IκB while enhancing the expression of IκB in MCF-7 and MDA-MB-231 cells. It also decreased the p-AKT/AKT and p-mTOR/mTOR ratios. Conclusion Our study demonstrated that baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting the PI3K/AKT signaling pathway in vivo and vitro. Our study revealed that baicalein may be a potential therapeutic agent for breast cancer.

https://www.dovepress.com/getfile.php?fileID=46256

Baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting PI3K/AKT pathway in vivo and vitro.

Background
The flavonoid baicalein, a historically used Chinese herbal medicine, shows a wide range of biological and pharmaceutical effects, among which its potent antitumor activity has raised great interest in recent years. However, the molecular mechanism involved in the antimetastatic effect of baicalein remains poorly understood. This study aimed to verify the inhibitory effects of baicalein on metastasis of MDA-MB-231 human breast cancer cells both in vitro and in vivo, as well as to investigate the related mechanisms.

Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway

Tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment and play an important role in cancer progression. Baicalein has a wide range of pharmacological properties. This study explores the potential effect of baicalein on macrophages polarization and epithelial-mesenchymal transition (EMT) of breast cancer. Co-culture system was established to evaluate the interaction between TAMs and breast cancer cells. Then the role of baicalein in modulating TAMs function was assessed. Finally, breast cancer mouse model was established to study the underlying mechanism. In vitro experiments showed that co-culture with M2 macrophages significantly enhanced EMT of both MDA-MB-231 and MCF-7 breast cancer cells. Baicalein could regulate polarization of M2 and attenuate TGF-β1 secretion. In vivo experiments showed that compared with the MDA-MB-231 + M2 group, tumor growth and metastasis of baicalein + MDA-MB-231 + M2 group was significantly inhibited, with smaller tumor size and decreased lung metastasis lesions. Our findings suggest that the regulation of TAMs may be a novel mechanism underlying the anti-tumor effects of baicalein in breast cancer.

Baicalein suppress EMT of breast cancer by mediating tumor-associated macrophages polarization.

// Hong Zhang 1 , Yafei Zhang 2 , Wanjun Yan 1 , Wen Wang 1 , Xixi Zhao 1 , Xingcong Ma 1 , Xiaoyan Gao 1 , Shuqun Zhang 1 1 Department of Oncology, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China 2 Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China Correspondence to: Shuqun Zhang, email: 15229326653@163.com Keywords: breast cancer, rs3746444, rs11614913, rs2910164, meta-analysis Received: October 20, 2016      Accepted: November 12, 2016      Published: November 17, 2016 ABSTRACT Three functional microRNA polymorphisms (miR-499 rs3746444 A > G, miR-196a rs11614913 C > T and miR-146a rs2910164 G > C) have been reported to be associated with breast cancer (BC) risk. However, the results of the published studies are inconsistent. In order to obtain a more credible result, we conducted this meta-analysis. We searched PubMed, EMBASE and Web of Science databases to identify relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association. Thirty-eight eligible studies with 17,417 cases and 18,988 controls were included in this meta-analysis. Our results showed that the rs3746444 was associated with an increased breast cancer risk in the four genetic models (G vs. A: OR = 1.17, P = 0.008; GG vs. AA: OR = 1.41, P < 0.001; AG vs. AA: OR = 1.10, P = 0.036; GG+AG vs. AA: OR = 1.16, P = 0.001). In the subgroup analysis by ethnicity, significant correlation remained in Asians but not in Caucasians. For rs11614913, obvious decreased breast cancer risk was observed in Caucasian populations (T vs. C: OR = 0.93, P = 0.044). However, we couldn't detect an association between rs2910164 and breast cancer risk. This meta-analysis demonstrates that rs3746444 could increase breast cancer risk in Asians and in general populations, while rs11614913 could decrease the risk of breast cancer in Caucasians. The rs2910164 polymorphism has no association with breast cancer risk. More multicenter studies with larger sample sizes are required to verify our results.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13426&path%5B%5D=42595

Association between three functional microRNA polymorphisms (miR-499 rs3746444, miR-196a rs11614913 and miR-146a rs2910164) and breast cancer risk: a meta-analysis.

// Wanjun Yan 1 , Xiaoyan Gao 1 and Shuqun Zhang 1 1 Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China Correspondence to: Shuqun Zhang, email: zhangshuqun1971@aliyun.com Keywords: miRNA, single nucleotide polymorphism, cancer susceptibility, meta-analysis Received: March 08, 2017      Accepted: August 29, 2017      Published: November 20, 2017 ABSTRACT Background: MicroRNAs (miRNAs) are small non-coding RNA molecules, which participate in diverse biological processes and may regulate tumor suppressor genes or oncogenes. Rs11614913 in miR-196a2 and rs3746444 in miR-499 are shown to associate with increased/decreased cancer risk. This meta-analysis was performed to systematically assess the overall association. Materials and Methods: We searched Pubmed, Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until December 2016 to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of the associations. Results: We assessed published studies of the association between these microRNA polymorphisms and cancer risk from 56 studies with 21958/26436 cases/controls for miR-196a2 and from 37 studies with 13759/17946 cases/controls for miR-499. The results demonstrated that miR-196a2 rs11614913 was significantly associated with a decreased cancer risk, in particular with a decreased risk for colorectal cancer and gastric cancer, or for Asian population subgroup. In addition, miR-499 rs3746444 polymorphism was observed as a risk factor for cancers, in particular, for breast cancer, or for in the Asian population. Conclusions: Our meta-analysis suggests that the rs11614913 most likely contributes to decreased susceptibility to cancer, especially in Asians and colorectal cancer and gastric cancer, and that the rs3746444 may increase risk for cancer. Furthermore, more well-designed studies with large sample size are still necessary to further elucidate the association between polymorphisms and different kinds of cancers risk.

/pdf/association-of-mir-196a2-rs11614913-and-mir-499-rs3746444-11kfwhil4v.pdf

Wanjun Yan

Papers

Baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting PI3K/AKT pathway in vivo and vitro.

Baicalein suppresses metastasis of breast cancer cells by inhibiting EMT via downregulation of SATB1 and Wnt/β-catenin pathway

Baicalein suppress EMT of breast cancer by mediating tumor-associated macrophages polarization.

Association between three functional microRNA polymorphisms (miR-499 rs3746444, miR-196a rs11614913 and miR-146a rs2910164) and breast cancer risk: a meta-analysis.

Association of miR-196a2 rs11614913 and miR-499 rs3746444 polymorphisms with cancer risk: a meta-analysis.