It all happened pretty quickly, and the truth is I just may owe my life to that. Oddly, I remember laughing with the technician who was working with me with my first ever mammogram experience. She was kind enough to chuckle as she tightened the glass plates that held my little bit of breast securely. Squeezing enough breast to get a good image was no easy task. I gained a deeper respect for women that day. He sent me across the hall for a biopsy. In less than 30 days from my original office visit I was dressed in a surgical gown, waiting my turn on the operating table.
I understand the controversy about mammograms. Detecting a tumor or even a lump in a man is relatively easy, so women rely more on the annual mammogram to discover breast cancer. Are they safe? Are they necessary? Do they save lives? I only know it probably saved mine. But there were many other factors that came into play. First and foremost was a sharp-eyed Osteopath—my first doctor in a quarter of a century. Good timing helped. Being self-employed all of my life I had no health insurance. Good timing is everything. So what have I learned, particularly where the mammogram is concerned?
Self-exams will save lives, but even that is a hard-sell where men are concerned. I wish I could change that. Khevin Barnes is a male breast cancer survivor and speaker. You present some wonderful personal perspective in male breast cancer screening, AND with wit and humor! Must reading. I deal with male breast cancer rather regularly in my consults dozens across the globe at any one time , so let me add a few a few points, drawn from personal experience in this arena over my many years as an oncology researcher with breast oncology as my specialty.
First, there is a place for mammography in men [Darkeh ] [Patterson ] [Swergold ], but the focus should necessarily be in high risk populations, which includes simplifying for sake of this discussion :. And there are many cases in which the non-imaging modalities like BSE breast self-examination and CBE clinical breast examination can miss important signals, as when there is extensive dense muscle tissue, or when a tumor can all too easily hide behind gynecomastia, and in these cases mammography is likely to be needed, even above ultrasound imaging which may lack the penetrance to detect the hidden lesion.
In addition, your experience was relatively positive and enlightened, but we still find in many smaller facilities, that men can be greeted with medical history forms often in pink asking about when they had their last menstrual cycle, so centers need to make the relevant accommodations in processing for male patients. COX inhibitors have potent activity in a model of highly aggressive breast cancer [ 61 ].
Epidemiologic and laboratory investigations suggest that non-steroidal anti-inflammatory drugs have chemopreventive effects against breast cancer due to their activity against COX-2, the rate-limiting enzyme of the prostaglandin cascade [ 62 ]. Inhibition of COX-2 and COX-1 results from the use of non-steroidal anti-inflammatory drugs and a case-controlled study has reported a reduction in the incidence of breast cancer in patients reporting a regular intake of these drugs [ 60 ]. VEGF2 is also a viable target for pharmacological intervention in cancer, and the aberrant expression of VEGF2 is a hallmark of malignant tumor development required for the colonization of endothelial cells that allow tumor nutrition [ 63 ].
Therefore, these high-degreed targets should be treated as the crucial ones of these herbs. Furthermore, mu-type opioid receptor and delta-type opioid receptor are also targeted by candidate components from 20 herbs, which have the effect of sedation. For this reason, OPRM1 mu-type opioid receptor genotype may play a key role in both the short-term postmastectomy outcome and the long-term follow-up, becoming a new biomarker for breast cancer recurrence in patients suffering from chronic postmastectomy pain managed by opioid therapy [ 64 ].
In addition, OPRD1 delta-type opioid receptor is also reported to have sedative effect [ 65 ]. Drug action is not only related to its targets, but also affects various metabolic enzymes, transporter proteins, as well as the downstream effects of drug action and pathways related to the specific disease. Multiple compounds can jointly perturb the same disease-related signal pathways [ 66 ]. For this reason, to understand the therapeutic mechanisms of a drug, it is also critical to identify the signal pathways its targets participate in.
Thus presently, network-based analyses among compounds, targets and pathways are carried out to study the pharmacological mechanism of the herb in a systematical level as well as to unfold the main targeting proteins and signaling pathways in the process of treatment. A link is created between a target and a pathway if the pathway is lighted at the target, where blue, green and red nodes represent compounds, targets and pathways, respectively.
The information of pathways is obtained by mapping the target proteins to the KEGG pathway database. The T-P network consists of nodes and edges, with blue, green and red nodes representing compounds, targets and pathways, respectively. Similarly, major pathways are also modulated through multiple target proteins, and many of them have been reported as suitable target pathways for breast cancer therapies, including the EGFR signaling pathway, Estrogen signaling pathway, and Wnt signaling pathway.
The three pathways are interdependent with each other through the compounds, indicating that the herbal medicines may exert synergistic influences through multiple different pathways. Of all 33 candidate targets, 24 participate in the EGFR signaling pathway, indicating that the EGFR signaling pathway plays an important role in the treatment of breast cancer. The signals mediated by EGFR can be deregulated by an increase in the amount of the receptor on the cell surface or by structural alterations of the protein that constitutively activates the signal pathway independent of its ligand [ 68 ].
IGF pathway is regulated in many critical points, from ligand availability to negative feedback mechanisms exerted by mTOR [ 68 ]. As for its role in human cancer, preclinical models show that the IGF1R is frequently overexpressed by tumors, and mediates proliferation and apoptosis protection [ 69 ]. Thus, the EGFR pathway participates in cell metabolism regulation, in growth and survival, and changes in this pathway may contribute to various subtypes of breast cancer [ 68 ].
The second pathway, Estrogen, also plays an important role in the growth and differentiation of the normal mammary gland [ 70 ]. However, there is considerable evidence that estrogens are also mammary carcinogens in the breast, involving the metabolism of estrogen to genotoxic, mutagenic metabolites and the stimulation of tissue growth [ 50 ]. Indeed, clinical and experimental studies have suggested an important role for Estrogen signaling pathway in the treatment of breast cancer and the reduction for estrogen deprivation of mammary tumors [ 70 ].
Therefore, given the role of this Estrogen signaling pathway in regulation of cell proliferation, mammary gland growth and development, estrogen is a major oncogenic factor and an attractive therapeutic target. The third pathway, Wnt signaling pathway plays an important role in modulating the inflammatory response and the regulation of many cellular processes, including cell fate decisions and cell proliferation, and aberrant Wnt signaling also is associated with tumorigenesis [ 73 , 74 ].
Moreover, studies in animal model systems clearly demonstrate that activated Wnt signaling leads to mammary tumorigenesis [ 74 ]. Thus, Wnt signaling contributes to the genesis of cancers in a wide range of human tissues. These findings reveal the importance of Wnt signaling pathway in inducing breast cancer. To sum it up, essential pathways for breast cancer mediate many of the characteristics of the malignant phenotype, such as increased cell proliferation, decreased apoptosis and metastasis. Since the three pathways are closely associated with epidermal growth factor receptor, estrogen receptor, and inflammatory, we speculate that the 20 herbs probably perturb the pathways, and thereby display anti-estrogen, anti-inflammatory, regulation of cell metabolism and proliferation activities.
The three pathways are interdependent with each other through compounds, which further indicate that 20 herbs can exert synergistic influences on different pathways Fig 5. In addition, a compound may target different proteins involved in the same pathway or different pathways, which also illustrates the mechanism of multiple targets for a TCM. Breast cancer is the most common malignancy in women.
Traditional Chinese medicine has been practiced for three thousand years. This discipline is practiced worldwide that TCM may serve as a useful model for scientific inquiry since there is a standardized system of diagnostics and therapies. However, unlike conventional pharmacological medications used in western medicine, bioactive compounds and mechanisms of action of herbal medications have not been specified and measured precisely. Thus, in the present study, we have constructed a systems pharmacology approach including the OB screening, DL evaluation, target identification, and network pharmacology analysis, which combines the use of computational modeling and wide-scale text-mining methods, to elucidate the mechanisms of action of the most widely studied medicinal herbs for the treatment of breast cancer.
The main findings are as follows:. Conceptualization: SC. Data curation: FL YY. Formal analysis: FL YY. Funding acquisition: YL. Methodology: SC YL. Project administration: SC. Resources: SC YL. Software: JW. Supervision: SC. Validation: JW. Visualization: JW. Writing — original draft: YL JW. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Breast cancer is the most common carcinoma in women. Introduction Over about one million people would have been diagnosed with cancer and , will have died of cancer during in the United States [ 1 ].
Materials and Methods As herbs usually contain considerable chemical compounds, databases of each herb were built firstly. Download: PPT. Table 1. Statistics and association analysis between 20 herbs and breast cancer. Chemical structures'construction. Oral bioavailability OB prediction Oral route, the mainly drug delivery system, is commonly used in the administration of herbal medicines.
Target prediction and validation Previously in our work, we have predicted the potential targets of human and viral origins based on a systematic model [ 14 ], which efficiently integrated the chemical, genomic and pharmacological information for drug targeting and discovery on a large scale based on two powerful methods of Random Forest RF and Support Vector Machine SVM. Network construction The analysis of networks has gained extensive attentions in biological and even TCM fields, due to the recent explosion of publicly available high-throughput biological data.
C-T network. T-P network. Physicochemical property analysis In order to analyze statistically the drug-like physicochemical properties of active compounds, herbal ingredient comparisons based on chemical properties are performed by considering 8 common molecular descriptors, which includes MW molecular weight , nCIC number of rings , nHDon number of hydrogen-bond donor , nHAcc number of hydrogen-bond acceptor , RBN number of rotatable bonds , Hy hydrophilic factor , TPSA topological polar surface area and MlogP Moriguchi octanol-water partition coefficient , since these parameters reflect the basic characteristics of molecules including especially their pharmacokinetic properties [ 17 ].
Fig 1. The profile distributions of eight important molecular properties for DrugBank drugs and herbal compounds. Table 2. Comparison of molecular properties between herbal compounds and DrugBank drugs. OB prediction and DL calculation For multi-compound medicinal herbs, it is usually quite difficult to distinguish those active ingredients from the compound pool of the TCMs due to the difficulties in current experimental methods, when virtual screening approaches are always of great help.
Table 3. Radix salvia. Atractylodes macrocephala koidz. Hedyotis diffusa. Drug targeting and validating for the therapy of breast cancer Identification of the protein targets of a bioactive small molecule is the most important step in new drug development because small molecules typically exert their bioactive effects through interactions with proteins. Fig 3. The global view of C-T network for the 20 breast cancer-related herbs.
The reasonability of the combination rule of Jun-Chen-Zuo-Shi. Illustrating the mechanism of action on treating breast cancer based on the C-T interactions.
MELK is not necessary for the proliferation of basal-like breast cancer cells | eLife
Fig 4. Distribution of the target proteins versus the drug node degree in the drug-target network. T-P network and systems analysis Drug action is not only related to its targets, but also affects various metabolic enzymes, transporter proteins, as well as the downstream effects of drug action and pathways related to the specific disease. Conclusion Breast cancer is the most common malignancy in women. The main findings are as follows: Through OB and DL screening, compounds out of components in 20 traditional Chinese medicines are identified as candidate compounds.
The rest herbs serve as assistant and messenger drugs. Three pathways are closely associated with epidermal growth factor receptor, estrogen receptor, and inflammatory. Therefore, we speculate that the 20 herbs display anti-estrogen, anti-inflammatory, regulation of cell metabolism and proliferation activities by probably perturbing these pathways. The T-P network of these herbs constructed presently demonstrates that the herbal medicines may simultaneously target several pathways like EGFR, Estrogen and Wnt signaling pathways, thereby exhibiting synergistic benefits in breast cancer treatment.
Supporting Information. S1 Table. The Candidate Compounds and their Candidate Targets. S2 Table. The values of eight important molecular properties for DrugBank drugs and herbal compounds. S3 Table. GOBP enrichment analysis for 33 potential targets of active compounds. Author Contributions Conceptualization: SC.
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