HomeENGLISH MAGAZINEAssaulting oncogenes and tumor suppressors, the additional targets to fight breast cancer

Assaulting oncogenes and tumor suppressors, the additional targets to fight breast cancer

The c-Myc oncogene is overexpressed in over 40% of breast cancers. This gene with a high potential for cancer initiation programs breast cancer cells to build more macromolecules by accelerating glucose metabolism and producing glutamine, an amino acid that serves for the production of nucleotide bases necessary for DNA synthesis. However, it also creates a metabolic vulnerability by making malignant cells more susceptible to programmed cell death known as apoptosis. Researchers are exploring the potential of this type of cell death by studying several known drugs as well as natural molecules. One of the “synergistic” drugs is venetoclax, a molecule that binds to the Bcl-2 protein which suppresses apoptosis. Bcl-2 is expressed in many aggressive carcinomas, also in breast cancers and has been approved for the treatment of some leukemias but not yet against breast cancer. In contrast, metformin has been identified in the search for drugs that could potentiate the lethal action of venetoclax in breast cancers.

Inhibition of apoptosis is a hallmark of cancer. Upregulation of survival proteins has been implicated in tumor growth and reduced sensitivity to anti-cancer therapy. Bcl-2 is an estrogen-responsive gene and is over-expressed in approximately 80% of primary ER-positive (ER+) breast cancers. It is a well known prognostic factor that can be easily assessed by special laboratory and genomic analyzes. Bcl-2, however, is often expressed at high levels in tumors with a poorer prognosis. Indeed, the annualized death rate following an early diagnosis of breast cancer is similar for ER or Bcl-2 positivity. Preclinical data from transplant models derived from ER+ breast cancer patients suggested that intermittent treatment with venetoclax synergized with tamoxifen to improve tumor response by increasing apoptosis. By treating cancer cells taken from patient biopsies with a combination of metformin + venetoclax, the size of the tumor shrinks and the killer lymphocytes ‘wake up’.

Metformin is a well-known antidiabetic drug that mimics the lack of energy in cells. It activates a signaling cascade that alters energy production and ultimately leads to apoptotic death. Metformin and venetoclax given together kill cultured breast cancer cells and stop tumor growth in animal models of breast cancer. However, the researchers soon found that treatment with metformin plus venetoclax only keeps the tumors in check if the mice are actively treated with the drugs. Once treatment is stopped, the tumors grow back. The researchers then realized that its drug combination exploits specific metabolic vulnerabilities that high levels of c-Myc create in cancer cells. More recently, another research team found that if naringenin is added to adriamycin, the basic anti-cancer antibiotic in the treatment of breast cancer, in addition to metformin, a lethal effect on the tumor is triple negative both in vitro and in vivo.

The combination made it possible to use lower doses of adriamycin, which is a toxic drug for the heart, and to add naringenin which is a naturally occurring polyphenol, specifically in citrus fruits such as oranges and grapefruits. Research against triple-negative cancer is much more extensive than research for estrogen-positive breast cancers. In fact, for triple-positive cancer, life expectancy for patients is much shorter than for other histological forms. This is because the triple-negative is not sensitive to anti-estrogens, progesterone antagonists and HER2 (tyrosine kinase) receptor inhibitors, which are the chemotherapy mainstays for breast cancers. Finally, research has been evaluating the potential of turmeric in this type of cancer for at least a decade. Its active ingredient, curcumin, is a potentially very effective anticancer, but has the disadvantage of being poorly bioavailable. This is why curcumin is found in commercial formulations associated with piperine, an alkaloid of black pepper that amplifies its solubility.

Currently, however, scientists use formulations that include curcumin inside liposomes, lipid structures that fuse with cell membranes ensuring direct delivery of the drug to cancer cells. Turmeric and some of its derivatives have the advantage of targeting several central cellular proteins for cell survival. Among these are precisely the c-Myc oncogene, the Bcl-2 oncogene and also the p53 tumor suppressor, whose activation in cancer cells leads them to arrest growth and then to programmed death. Therefore, there are several options with synthetic drugs and natural molecules being studied aimed at selectively interfering with cancer cells, more specifically than with the old chemotherapy treatments of the past. The main issue lies in finding the right combination that can show efficacy and safety at the same time.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Clinical Biochemistry.

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Scientific references

Kostrzewa T et al. Int J Mol Sci. 2021; 22(19):10368.

Xue L et al. Breast Cancer Res Treat. 2021; 185(1):73.

Yin L, He Z et al. Front Pharmacol. 2020; 11:574068.

Uchida A et al. Haematologica 2019; 104(7):1417-21.

Matulis SM et al. Leukemia 2019; 33(5):1291-1296.

Haikala HM et al Nature Commun 2019; 10(1):620.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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