Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development.

Molecular targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells process a fundamental change in its bioenergetic metabolism from normal cells on an altered lipid metabolism, also known as the de novo fatty acid synthesis, for sustaining their high proliferation rates. Fatty acid synthesis is now associated with clinically aggressive tumor behavior and tumor cell growth and has become a novel target pathway for chemotherapy development. Although the underlying mechanisms of the altered de novo fatty acid synthesis still remains unclear, recent progress has shown that by targeting Fatty acid synthase (FASN), a key enzyme that catalyzes the synthesis of endogenous long chain fatty acid could be a critical target for drug discovery. However, relatively few FASN inhibitors have been discovered. With the long history of clinical practices and numerous histological case study reports, traditional Chinese medicine enjoys an important role in seeking bioactive anticancer natural compounds. Herein, we will give an overall picture of the current progress of molecular targeted therapy in cancer fatty acid synthesis, describe the advances in the research on natural products-derived FASN inhibitors and their potential for enhancing our understanding of fatty acids in tumor biology, and may provide new therapeutic moieties for breast cancer patient care.

BackgroundChinese herbal medicine is increasingly widely used as a complementary approach for control of breast cancer recurrence and metastasis. In this paper, we examined the implicit prescription patterns behind the Chinese medicinal formulae, so as to explore the Chinese medicinal compatibility patterns or rules in the treatment or control of breast cancer recurrence and metastasis.MethodsThis study was based on the herbs recorded in Pharmacopoeia of the People’s Republic of China, and the literature sources from Chinese Journal Net and China Master Dissertations Full-text Database (1990 – 2010) to analyze the compatibility rule of the prescription. Each Chinese herb was listed according to the selected medicinal formulae and the added information was organized to establish a database. The frequency and the association rules of the prescription patterns were analyzed using the SPSS Clenmentine Data Mining System. An initial statistical analysis was carried out to categorize the herbs according to their medicinal types and dosage, natures, flavors, channel tropism, and functions. Based on the categorization, the frequencies of occurrence were computed.ResultsThe main prescriptive features from the selected formulae of the mining data are: (1) warm or cold herbs in the Five Properties category; sweet or bitter herbs in the Five Flavors category and with affinity to the liver meridian are the most frequently prescribed in the 96 medicinal formulae; (2) herbs with tonifying and replenishing, blood-activating and stasis-resolving, spleen-strengthening and dampness-resolving or heat-clearing and detoxicating functions that are frequently prescribed; (3) herbs with blood-tonifying, yin-tonifying, spleen-strengthening and dampness-resolving, heat-clearing and detoxicating, and blood-activating with stasis-resolving functions that are interrelated and prescribed in combination with qi-tonifying herbs.ConclusionsThe results indicate that there is a close relationship between recurrence and metastasis of breast cancer with liver dysfunctions. These prescriptions focus on the herbs for nourishing the yin-blood, and emolliating and regulating the liver which seems to be the key element in the treatment process. Meanwhile, the use of qi-tonifying and spleen-strengthening herbs also forms the basis of prescription patterns.

Aims The aim of the present study is to investigate whether the aqueous extract from Huaier, a traditional Chinese medicine (TCM), can affect the expression of Duffy antigen receptor for chemokines (DARC) and its ligands. Moreover, we compare the status of DARC in primary and metastatic breast cancer tissues from the same patient. Methods Immunohistochemistry was used to detect the expression of DARC in primary and metastatic focuses in 30 patients with breast cancer. The effect of Huaier aqueous extract on the expression of DARC and its ligands was investigated by quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Results The expression score of DARC in primary focuses was significantly higher than that in metastatic focuses, while changes of ER, PR, and HER2 receptors were not significantly different between primary and metastatic focuses. Huaier aqueous extract promoted the expression of DARC and reduced the secretion of CC chemokine ligand 2 (CCL-2), CXC chemokine ligand 8 (CXCL-8, IL-8), matrix metalloproteinase 2 (MMP-2), and CXC chemokine ligand 1 (CXCL-1). Conclusion The present study demonstrates that difference in expression level of DARC between primary and metastatic focuses of breast cancer was significant, while differences in expression of ER, PR, and HER2 between primary and metastatic focuses were not significant. DARC may play a negative role in the metastasis of breast cancer. Traditional Chinese medicine extract from Huaier can increase DARC expression and reduce the expression of its ligands such as CCL-2, IL-8, MMP-2, and CXCL-1.

Chemoprevention plays an important role in the prevention of cancer. Due to being an estrogen-dependent cancer, breast carcinomas are ideal candidate for chemoprevention. The two main approaches to chemoprevention of breast cancer are to attain a balance in estrogen or to eliminate all estrogens by selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). A series of clinical trials have proven tamoxifene quite useful as a preventive strategy for women at high risk of breast cancer. The third-generation, AIs, hold a great promise in chemoprevention of breast cancer. In this review, the mechanisms, side effects and main clinical trials of SERMs and AIs are discussed. The use of other drugs including CoQ10, retinoids, cyclooxygenase (COX)-2 inhibitors, vitamin E, soy isoflavones, tea polyphenols and statins in chemoprevention is introduced. Since most studies on these drugs were conducted on animal models or cell culture, further studies are needed to determine the efficacy of these drugs in chemoprevention of human cancers.

Background Emerging studies have identified chronic psychological stress as an independent risk factor influencing breast cancer growth and metastasis. However, the effects of chronic psychological stress on pre-metastatic niche (PMN) formation and the underlying immunological mechanisms remain largely unknown. Methods The effects and molecular mechanisms of chronic unpredictable mild stress (CUMS) on modulating tumor-associated macrophages (TAMs) and PMN formation were clarified by multiplex immunofluorescence technique, cytokine array, chromatin immunoprecipitation, the dual-luciferase reporter assay, and breast cancer xenografts. Transwell and CD8+ T cytotoxicity detection were used to analyze the mobilization and function of myeloid-derived suppressor cells (MDSCs). mCherry-labeled tracing strategy and bone marrow transplantation were applied to explore the crucial role of splenic CXCR2+/+ MDSCs facilitating PMN formation under CUMS. Results CUMS significantly promoted breast cancer growth and metastasis, accompanied by TAMs accumulation in the microenvironment. CXCL1 was identified as a crucial chemokine in TAMs facilitating PMN formation in a glucocorticoid receptor (GR)-dependent manner. Interestingly, the spleen index was significantly reduced under CUMS, and splenic MDSCs were validated as a key factor mediating CXCL1-induced PMN formation. The molecular mechanism study revealed that TAM-derived CXCL1 enhanced the proliferation, migration, and anti-CD8+ T cell functions of MDSCs via CXCR2. Moreover, CXCR2 knockout and CXCR2−/−MDSCs transplantation significantly impaired CUMS-mediated MDSC elevation, PMN formation, and breast cancer metastasis. Conclusion Our findings shed new light on the association between chronic psychological stress and splenic MDSC mobilization, and suggest that stress-related glucocorticoid elevation can enhance TAM/CXCL1 signaling and subsequently recruit splenic MDSCs to promote PMN formation via CXCR2. Graphical Abstract

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Background: Emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods: Apoptotic breast cancer cells induced by paclitaxel treatment were sorted and their released exosomes (exo-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in exo-dead. Zebrafish and mouse xenograft models were used to investigate the effect of exo-dead on breast cancer progressionin vivo. Multiple molecular biological experiments were conducted to determine the underlying mechanisms of exo-dead in promoting breast cancer, as well as its intervention values. Results: It was demonstrated that exo-dead were phagocytized by macrophages and induced breast cancer metastasis by promoting the infiltration of immunosuppressive PD-L1+TAMs. Chemokine array identified CXCL1 as a crucial component in exo-dead to activate TAM/PD-L1 signaling. Exosomal CXCL1 knockdown or macrophage depletion significantly inhibited exo-dead-induced breast cancer growth and metastasis. Mechanistic investigations revealed that CXCL1exo-deadenhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting exosomal CXCL1 signals to enhance paclitaxel chemosensitivity and limit breast cancer metastasis without noticeable toxicities. Conclusions: Our results highlight CXCL1exo-deadas a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve breast cancer prognosis.