Why RNAi can be a solution to breast cancer

PC_BreastCancerThe word “Cancer” (or malignant tumour or neoplasm) refers to a large group of diseases that can affect any part of the body. It is characterized by rapid creation of abnormal cells that overgrow by invading the organ from which they originated (formation of the primary tumour) and spread to other organs where can give arise to secondary tumours (metastases) which are the major cause of death from cancer 1.

Cancer is a major disease and cause of death worldwide, accounting for 8.2 million deaths in 2012 2. On the same year, Breast cancer accounted nearly 1.7 million new cases diagnosed, being the most common cancer in women worldwide 3, and the fifth type of cancer worldwide leading to death 2.

Despite the awareness of the women nowadays and the many organization promoting screening initiatives (e.g. The Breast Health global Initiative), the recurrence rate and frequency of metastatic disease caused by breast cancer remain high 4.

Big problems of breast cancer are the absence of symptoms until advanced stages and its high potential to quickly develop metastasis 5. Apart from the screening, this is fortunately leading to decrease of mortality, helping to diagnose the disease in time, prevention is difficult for breast cancer, being this pathology mainly hormonal related 3. Moreover at the therapeutic level, much more progress needs to be achieved. Breast cancers are indeed malignant solid tumors, which are usually treated surgery, and/or radiotherapy, and/or classical chemotherapy, which are able to remove the primary tumor and to reduce or remove the secondary tumors but which have low or no effect on the possibility of recurrence.

The limitation of the classical therapy relies on the complexity of the biochemistry behind the development of breast cancer.

Analogously to other solid tumors, breast cancer arises though a multistep process, which allows the normal cells to accumulate mutations, which confer to them selective advantages. Recent evidence suggests that a limited number of tumor cells called cancer stem cells (CSCs) is capable of driving tumorigenesis and via asymmetric division creates a heterogeneous tumor population with cells of various differentiation grades. Current breast cancer therapies target the bulk of the tumor mass, leaving the stem-like cell population intact due to their chemo- and radiation-resistance capabilities 6. Other than being able to regenerate the tumor, the CSCs are able to spread to other parts of the body and they are considered to be responsible for the formation of the metastasis 7. Thus, to improve the prognosis and to reduce the possibility of metastasization and tumor recurrence, the design of therapeutics targeting BCSCs (breast cancer stem cells) would be the best way.

Since its discovery in 2006, for which Andrew Z. Fire and Craig C. Mello were awarded for The Nobel Prize in Physiology or Medicine , the RNA interference (RNAi), has being considered to be a promising tool for cancer targeting.

RNA interference (RNAi) is a regulatory mechanism of eukaryotic cells that uses small double stranded RNA known as small interfering RNAs (siRNA) to regulate gene activity. These ∼21– 22 bp long dsRNA molecules have a characteristic 2 nucleotide 3′ overhang that allows them to be recognized by the enzymatic machinery of RNAi, the RISC complex, which leads to the digestion of the targeted mRNA, complementary to the antisense strand of the siRNA 8.

Considering this mechanism, ideally, any mRNA can be digested if a corresponding siRNA is designed and delivered to the cell.

Currently, progress has been achieved to characterize the most accurate BCSC genotype, in order to discover oncogenes that could be knocked down by using tools like the RNAi.  Studies indicates that a typical BCSC genotype is CD44+/CD24- , ALDH1High, OCT4+, SOX2+ and NANOG+ 9.

On the bases of what said until now, it seems to be reasonable to design a strategy that uses RNAi and to target BCSCs through the upregulated genes. However, despite RNAi is promising in vitro, it presents some limitations in vivo which have to be overcome to succeed 8 :

  • Low stability in vivo due to RNAse degradation
  • Low potential to overpass the membranes due to negative charge which repulse them
  • Stimulation of innate immune response

Nowadays one of the biggest challenges for the scientific community is directed to design a good delivery system to administer the siRNA in vivo, which would allow not only breast cancer but also other gene-related pathologies to be cured by using the powerful RNAi tool.

Martina Tuttolomondo 
PhD student, PathChooser Fellow
University of Southern Denmark

References:

  1. World Health Organization. Cancer Fact sheet N°297. (2014). at http://www.who.int/mediacentre/factsheets/fs297/en/
  2. Stewart, B. W. & Wild, C. P. World Cancer Report 2014. World Health Organization: Geneva (2014). doi:9283204298
  3. World cancer research fund international. Breast cancer statistics. (2015). at http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breast-cancer-statistics
  4. SEER. SEER Stat Fact Sheets: Female Breast Cancer. (2015). at http://seer.cancer.gov/statfacts/html/breast.html
  5. Di, D. et al. Early detection of tumor recurrence in patients with asymptomatic breast cancer with tumor marker kinetics and whole body imaging. Journal of Clinical Oncology 29, – (2011).
  6. Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. U. S. A. 106, 13820–13825 (2009).
  7. Sampieri, K. & Fodde, R. Seminars in Cancer Biology Cancer stem cells and metastasis. Semin. Cancer Biol. 22, 187–193 (2012).
  8. Aagaard, L. & Rossi, J. J. RNAi therapeutics: Principles, prospects and challenges. Adv. Drug Deliv. Rev. 59, 75–86 (2007).
  9. Klevebring, D. et al. Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo. Breast Cancer Res. 16, R72 (2014).
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