Cannabinoids for the Treatment of Breast Cancer
Breast cancer is the most common form of cancer among woman and the leading cause of death in woman between the ages of 40 and 44. With all the years of research and publicity, breast carcinoma is increasing in the United States with an estimated 178,000 new cases each year (Jadack, 2013). As with any disease, it is imperative to identify the risk factors and treat the underlying cause of the cancer. Risk factors for breast cancer include synthetic hormone replacement therapies, hormonal imbalances, and reproductive factors including age when given birth and if the infant was breast fed, family history of breast cancer, age cancer was acquired and other factors including radiation exposure to electromagnetic fields, viruses (Jadack, 2013) and environmental toxicity which interferes with endocrine function. Research on the use of cannabinoids for the treatment of cancer is exploding with clinical human trails funded by the Israeli Government being conducted in Israeli hospitals. Historically, Cannabinoids were used by the medicinal profession for many disorders. In 1933, Harry J Anslinger, the Commissioner of the Federal Bureau of Narcotics began a campaign and cannabis and cannabinoids were outlawed in 1937 by the Unites States government. We will discuss how cannabinoids impact cancer cells and review the current research on the use of cannabinoids for the treatment of breast cancer.
Mechanism of Action
Cancer is a disorder of gene expression resulting in genetic mutations which alter a normal cell and transform it by numerous ways to a cancer cell. Cancer cells multiply and form tumors that can also metastasize to invade other organ systems. When a cell becomes diseased or modified, it typically dies by the suicide process known as apoptosis. Cancer cells evade the normal rules of apoptosis which allows them to proliferate. For example, cancer may arise when tumor suppressor gene functions fails allowing the tumor cell to proliferate (Banasik, 2013). Generally, any cellular alteration that promotes proliferation or inhibits apoptosis can contribute to tumor development (Banasik, 2013).
Recently, scientists discovered that the human body has an endocannabinoid system which supports homeostasis by regulating many bodily functions in the brain and throughout the body. Although the body can synthesize endocannabinoids, cannabinoids can also be acquired through the diet via cannabinoid oil from the hemp plant. Endocannabinoids and cannabinoids are bioactive lipids that are mediated by receptors CB1 and CB2 with other systems also identified. We will focus on CB2 receptors which are known to support the immune system and protect the body from cancer through the regulation of apoptosis. When a cell becomes cancerous, it releases an abundance of CB2 receptors on its cell membrane which signal cannabinoid binding. This binding activates numerous signaling mechanisms that result in apoptosis of cancer cells.
One such signaling mechanism of CB1 or CB2 activation is the synthesis of ceramide in human tumors (Hermanson & Marnett 2011). Ceramide is a pro-apoptotic lipid that regulates stress proteins and genes within the endoplasmic reticulum. CB1 and CB2 activation leads to increased ceramide levels and activating complex signaling pathways that shut down mitochondrial production and induce apoptosis (Hermanson & Marnett, 2011).
Cannabinoid’s and Breast Cancer
Cannabinoid studies have demonstrated than binding to CB2 promotes antitumor and anti-proliferation of cancer. Recently, cannabinoid agonists have been shown to inhibit tumor migration and metastasis in human breast and prostate cancer cells by deactivating the G-protein-coupled chemokine receptor CXCR4 which signals cancer cell migration, proliferation and metastasis to distal organs (Coke & Scarlett & Chetram et al. 2016). Coke et al (2016) postulated that metastatic regulation via CXCR4 may result from GPCR heterodimerization with CB2 alterations in signaling and or function. Ohio State University researchers, Elbaz & Nasser, & Ravi et al (2015) found that CBD inhibits breast cancer growth and metastasis by inhibiting epidermal growth factor (EGF) induced proliferation and chemotaxis in breast cancer cells. The general mechanism by which CBD is able to prevent metastasis is through the inhibition of EGF/EGFR signaling and modulating the tumor microenvironment.
Breast cell tumor expression of HER2+ from the Leukemia virus shows poor patient prognosis and survival (Perez-Gomez & Andradas & Blasco-Benito et al. 2015). Perez-Gomez et al (2015) found that HER2 and CB2 form heteromers in cancer cells and that CB2 is a critical regulator of the HER2 pro-oncogenic signaling in breast cancer. They found that HER2 upregulates CB2 expression through activation of transcription factors ELK1 via the ERK cascade which activates HER2 pro-oncogenic signaling of tyrosine kinase c-SRC.
An aggressive breast cancer called triple negative breast cancers (TNBC) results in poor prognosis. A synthetic blend of Quinone/cannabinoid pharmacophores showed efficacy of inducing apoptosis of human TNBC cells through activation of CB2 receptors and oxidative stress (Morales & Blasco-Benito & Andradas, 2015). In another study, cannabidiol was shown to significantly inhibit epidermal growth factor (EGF) – induced proliferation and chemotaxis of TNBC breast cancer cells (Elbaz et al 2015).
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Coke, C. J., Scarlett, K. A., Chetram, M. A., Jones, K. J., Sandifer, B. J., Davis, A. S., . . . Hinton, C. V. (2016). Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and Cannabinoid receptor 2 (CB2) reveal a mechanism for regulation of tumor progression. The Journal of Biological Chemistry. doi:pii: jbc.M115.712661
Elbaz, M., Nasser, M. W., Ravi, J., Wani, N. A., Ahirwar, D. K., Zhao, H., . . . Ganjy, R. K. (2015). Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of Cannabidiol in breast cancer [Abstract]. Molecular Oncology, 906-19. doi:10.1016/j.molonc.2014.12.010
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Morales, P., Blasco-Benito, S., Andradas, C., Gomez-Canas, M., Flores, J. M., Goya, P., . . . Jagerovic, N. (2015). Selective, nontoxic CB(2) cannabinoid o-quinone with in vivo activity against triple-negative breast cancer [Abstract]. Journal of Medical Chemisty, 2256-64. doi:10.1021/acs.jmedchem.5b00078
Perez-Gomez, E., Andradas, C., Blasco-Benito, S., Cafffarel, M. M., Garcia-Taboada, E., Villa-Morales, M., . . . Sanchez, C. (2015). Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer [Abstract]. Journal of the National Cancer Institute. doi:10.1093/jnci/djv077