Breast cancer will affect 1 in 8 woman during their lifetime and is the most common cancer among females worldwide, according to the World Health Organization. Breast cancer occurs when malignant cells are formed in the mammary tissue and spreads to form tumors. Early detection by physical examination or a mammography increases survival rates; however survival rates are also dependent on the breast cancer type and sufferers age. There have been significant advances in diagnostics over the years meaning breast cancer is usually easy to detect.

breast cancer

 

Knowledge of how a primary breast cancer tumor becomes an advanced metastatic tumor however is lacking, resulting in a limited number of treatment options available [1]. How breast cancer cells and primary mammary epithelial cells interact and communicate with each other to promote tumorigenesis has been a topic of discussion among researchers.

Exosomes Involved in Metastasis

Exosomes are nanoparticles made up of constituents including microRNA, mRNA and proteins from the donor cell they have originated from and are capable of influencing the phenotype of recipient cells. Dutta and colleagues carried out research to conclude if exosomes are produced by breast cancer cells to communicate and manipulate mammary epithelial cells; a process called cross-talk [1].

The interactions between exosomes and 3 different breast cancer cells lines and primary mammary epithelial cells were studied in conditioned media. The results showed that exosomes produced by the 3 different types of breast cancer cells were taken up by the primary mammary epithelial cells, resulting in the production of reactive oxygen species (ROS) and autophagy. The interaction between the carcinoma cells and the primary mammary cells also caused phosphorylation of several proteins, indicating DNA damage repair. Another interesting result was after communication from the cancer cells with the primary mammary epithelial cells, the mammary cells produced breast cancer promoting factors.

All the evidence collected by Dutta's team indicates that exosomes are responsible for communication between cancer cells and primary mammary epithelial cells, causing them to produce promoting factors and reactive oxygen species, to create a tumor permissive microenvironment. The discovery of exosome involvement in breast cancer metastasis generates a novel research path in drug development to prevent breast cancer.

Exosomes and Drug Resistance

An increasing issue in recent years has been the matter of breast cancer drug resistance. The over-expression of the protein HER-2 (human epidermal growth factor receptor 2) has been known to promote cancer cell growth and occurs in approximately 25% of breast cancer cases [3]. There have been several drugs therefore developed to target the HER-2 protein, for example the monoclonal antibody trastuzumab, however not all patients are responsive or develop drug resistance, presenting a clinical challenge.

Rani and colleagues at Trinity College in Dublin have been carrying out research based on finding a exosome biomarker for HER-targeting drugs in order to improve patient selection and help prevent drug resistance [2]. Whilst studying the breast cancer cells exosomes (or extracellular vesicles) the team discovered a molecule called Neuromedin U (NmU), found to have a strong correlation with drug resistance to new HER-2 targeted drugs. This suggests its use as a biomarker for resistance in HER-2 positive breast cancer patients.

Using NmU as an extracellular blood-based biomarker would be of real benefit to patients as a simple, non-invasive blood test could reveal if they are suitable for HER-2 targeted drugs or whether they have a resistance and need to follow an alternative treatment plan.

The discovery of this biomarker could also help ease the problem of drug resistance as the researchers found if the level of NmU was altered, sensitivity to HER-2 targeting drugs could be increased.

Research into exosomes involvement in breast cancer and their biomarker use has been a rapidly increasing area of research, especially in the last few years. Exosomes are helping to shed light on how breast cancer spreads and providing biomarkers for the issue of drug resistance. Proposed research plans at Stanford University aim to manipulate the use of exosomes to deliver therapeutic mRNA for HER-2 enzyme pro-drug therapy. Hopefully with more research, an increased range of treatments will be available to patients and the serious issue of drug resistance can be circumvented.

 

Citations:

[1] Dutta, S. et al. Interactions between Exosomes from Breast Cancer Cells and Primary Mammary Epithelial Cells Leads to Generation of Reactive Oxygen Species Which Induce DNA Damage Response, Stabilization of p53 and Autophagy in Epithelial Cells. (2014). PLoS ONE. 9: e97580.

[2] Rani, S. et al. Neuromedin U: A Candidate Biomarker and Therapeutic Target to Predict and Overcome Resistance to HER-Tyrosine Kinase Inhibitors. (2014). Cancer Res74: 3821.

[3] Slamon, D.J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. (1987). Science. 235:177–82.

Photo courtesy of www.nationalbreastcancer.org