South Australian scientists have made a critical breakthrough, discovering how an obscure protein causes breast cancer to develop and grow more quickly. High levels of a protein called Creld2 have been linked to the most aggressive types of breast cancer with lower survival rates, according to Associate Professor Michael Samuel, a senior UniSA researcher in the Centre for Cancer Biology (CCB), who spearheaded this research with co-lead scientist Dr Marina Kochetkova. Scientists have been aware of this protein for some time, but it has not been well-studied and until now we hadn’t understood the role it plays in breast cancer. Creld2 appears to make normal, healthy cells surrounding the tumor behave abnormally, causing them to help tumors grow. In a paper published in Nature Cell Biology today, the researchers describe how aggressive breast cancers produce Creld2, which hijacks healthy cells, to promote tumor progression. High levels of Creld2 are found in triple-negative breast cancers, which make up between 15-20% of all breast cancers worldwide, are difficult to treat and have the poorest survival rates due to lack of sensitivity to common anti-hormone therapy and highly invasive rate. This type of breast cancer also frequently affects younger women.
Creld2 at high levels is also found in kidney cancers, non-melanoma skin cancers and invasive squamous cell carcinomas, which can be deadly if not detected early. Associate Professor Michael Samuel, Senior UniSA researcher in the Centre for Cancer Biology (CCB) and his alliance team between the University of South Australia and SA Pathology, is now working on therapies to destroy or block Creld2, with the aim of stopping breast cancers from growing and spreading around the body. Another team of researchers led by Worcester Polytechnic Institute (WPI) Provost Wole Soboyejo, instead, has identified targeted drugs that reduced the sizes of hard-to-treat breast cancer tumors in mice without inducing the toxic side effects that are typically associated with conventional chemotherapy. The researchers said in an article published in Scientific Reports that a molecular recognition unit attached to drugs specifically targeted “triple-negative” breast cancer tumors, which typically do not respond to targeted therapies. The targeted drugs eliminated or reduced the sizes of breast cancer tumors in laboratory experiments that were performed on mice. No toxic side effects were observed in the experiments.
When injected into the bloodstream, only a small fraction of traditional chemotherapeutic drugs reaches tumors. It usually takes relatively high concentrations of conventional cancer drugs to have therapeutic effects on tumors. Hence, such concentrations are often toxic to other cells. In our case, the targeting drugs were more effective at shrinking and eliminating triple-negative breast tumors in mice. They also eliminated tumors without inducing toxicity. Chemotherapy kills fast-growing breast cancer cells by flooding a patient’s body with potent drugs, but the treatment often produces toxic side effects. Targeted therapy aims to reduce side effects by delivering chemotherapeutic drugs directly to breast cancer tumor cells. The drugs seek out and bind to specific cellular structures known as receptors. Three common receptors that are over-expressed on breast cancer cells are HER2, as well as estrogen and progesterone receptors. Most breast cancer treatments target HER2 receptors. However, between 10% and 17% of all breast cancers lack HER2, estrogen, and progesterone receptors. These “triple-negative” breast cancers are more prevalent in younger women, African and African American women.
Soboyejo, inspired by a relative’s battle with breast cancer, previously studied luteinizing hormone-releasing hormone (LHRH) as a targeting mechanism to deliver magnetic nanoparticles to breast tumors. The targeted magnetic nanoparticles were found to improve the imaging of breast tumors in nude mice, a type of laboratory mouse. LHRH is a naturally occurring hormone in mammals that is essential for reproduction. More recently, Dr. Soboyejo began studying LHRH as a targeting mechanism for chemotherapeutic drugs. In this study, the researchers attached the chemotherapy drug paclitaxel to LHRH. They also attached to LHRH a natural antibiotic with anti-cancer properties, called prodigiosin. Both combination molecules were tested against triple-negative breast cancer cells and tissues. The team hopes to continue work on LHRH-targeted nanoparticles and therapeutic drugs, and to position them for human clinical trials on breast cancer patients. The group is also working to identify other targeted drugs and nanoparticles for the detection and treatment of other tumors.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Boyle ST et al. Nature Cell Biology 2020 May 25.
Obayemi JD et al. Sci Reports 2020 May; 10(1):8212.
Hegab AE et al. J Pathol 2019; 249(2):193-205.
Danyuo Y, Ani CJ et al. Sci Rep. 2019 Mar; 9(1):3862.
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