Smoke, drink tea, and be cancer free?

The future in breast cancer treatment

Leanne Fogg

As discussed in my previous blog post, the cannabinoids control our psychophysiological conditions, acting as neuromodulators within the central nervous system. I am grateful for my endocannabinoids, as I enjoy a good runner’s high, but my love for them grew when I discovered their potential in cancer therapy. Let’s just say they are kind of a big deal.

A refresher on cancer

Normal cells respond to stimuli, perform appropriate functions, and follow typical cell cycles. Cancerous cells do not abide by the rules – they have the ability to rapidly proliferate, avoid apoptosis, and can metastasize and invade distant tissues, disseminating infection. Not all cancers are the same, as numerous mutations and alterations in gene expression can allow cells to overcome barriers that would otherwise hinder them as “normal.”

Cannabinoids and cancer

In peripheral and nervous tissue, activation of a cannabinoid receptor can lead to alterations in intracellular signaling pathways, resulting in the inhibition of several types of cancer growth including glioma, glioblastoma multiforme, breast, prostate, colon carcinomas, leukemia and lymphoid tumors. Research of cannabinoids as cancer treatment has been studied predominately in breast cancer models, as the cannabinoid system influences hormonal cues that can lead to cancer.

Breast cancer statistics
One of the highest incidence rates world wide occurs in the United States, affecting about one in every eight (12%) women. The American Cancer Society estimates that in 2013, about 230,000 women will be diagnosed with invasive breast cancer. Improvements in treatments are necessary, as about 40,000 women are predicted to die from breast cancer this year.

Breast cancer incidence rates world wide (http://www.worldwidebreastcancer.com)

Therapies in the form of hormonal targeting, cannabinoid system activation, and even anti-cancer dietary supplements have proven to be promising forms of breast cancer treatment. Taking a closer look at the role of the endocrine system in the development of breast cancer can provide us with a physiological perspective in disease treatment.

Endocrine system and breast cancer

Hormones are chemical messengers secreted into the blood that regulate cellular functions such as metabolism, growth, and differentiation. Proper endocrine function is required to maintain homeostasis of an organism. Problems begin to develop when hormonal concentrations are not appropriate, or when cellular sensitivity to hormones is abnormal.

Breast cancer progression is in part attributed to the signal transduction pathway initiated by prolactin (PRL) – a hormone that induces numerous changes including cell growth, differentiation, and survival. PRL will bind prolactin receptors (PRLRs) on the cell surface, triggering a change in gene expressions. Excessive stimulus by prolactin allows cells to take on cancerous phenotypes, contributing to the growth and dissemination of the disease. 

Prolactin binding induces cancer characteristics (Goffin 2005)

But do not fear… cannabinoids are here!
About 60-70% of breast cancer subtypes over express cannabinoid receptors (CB1 and CB2), allowing for the specific targeting of cancer cells by cannabinoids. Natural and synthetic cannabinoids have demonstrated their ability to activate CB1 receptors and trigger anti-cancer responses. Among these CB1 agonists include THC (the main psychoactive ingredient in marijuana), anandamide (AEA), and 2-methyl-2’-F-anandamide (Met-F-AEA). Met-F-AEA is commonly used in lab studies, as it is a metabolically stable equivalent of the natural endocannabinoid AEA, and has potential to be used in drug treatment.

CB1 cannabinoid receptor activation results in cell cycle arrest and a decreased expression of prolactin receptors. Cell cycle arrest occurs at the G₁ to S phase transition through activation of Chk1 (a cell cycle regulatory protein), inhibiting the proliferative characteristics of the cancerous cell. Upon activation of CB1, inhibition of adenylyl cyclase and the ERK cascade lead not only to cell cycle arrest, but also the down-regulation in prolactin receptor expression. Without receptors on the surface of the cell, prolactin cannot perform alterations in gene expression that would otherwise give rise to a cancerous cell.

Cannabinoids inhibit proliferation, migration, invasion, and down-regulate expression of prolactin receptors (Caffarel 2012)

Cannabinoids also inhibit metastasis, decreasing migration and invasion of cancer cells. Met-F-AEA demonstrated this effect in a mouse model by regulating the phosphorylation FAK and Src (proteins involved in forming focal adhesion complexes). Forming focal adhesions are important in metastasis, as migratory cells need to adhere to a surface to effectively disseminate infection. A decrease in motility of cells will also prevent metastases, and infected cells will not travel as far from the primary infection. Adhesion and motility was restored with addition of SR141716A (a selective CB1 antagonist), suggesting CB1 activation is responsible for the inhibition of metastatic characteristics.

Met-F-AEA (AEA) decreases metastases in vivo (Grimaldi 2006)

Alternative treatments
Although several cannabinoids have proven their anti-cancerous properties, other forms of therapies offer potential alternatives in the treatment of breast cancer. In December 2012, Damiano et al. demonstrated a more direct form of treatment in the prevention of prolactin-induced cancer. Instead of activating the cannabinoid system, researchers used a monoclonal antibody (LFA102) to target the extracellular domains of prolactin receptors. LFA102 was shown to inhibit prolactin binding in vitro and in vivo, and is currently in phase 1 clinical trials.

Another hormone known to promote cancer is estrogen – the primary female sex hormone. As with prolactin, high hormonal plasma levels correlate with an increased risk for breast cancer. By stimulating estrogen receptors, activation of ERK cascade leads to increased invasion and migration in breast cancer cells. Treatments have targeted various components of the estrogen system, preventing estrogen-induced cancer. 

Left: visualization of active ERK1/2 with rabbit antibody in various breast cancer  tissue samples
Right: ERK1/2 is activated by phosphorylation in estrogen-induced cancer (Ohshiro 2012)

Hormonal therapies have been effective for several types of breast cancer through the inhibition of estrogen – either through inhibiting the biosynthesis of estrogen or by blocking the binding of estrogen to its receptor.

Tamoxifen is selective estrogen receptor modulator (SERM), commonly used in the treatment of ER⁺ breast cancers (cells express estrogen receptors). A metabolite of Tamoxifen (hydroxytamoxifen) acts as an estrogen receptor antagonist in breast cells, inhibiting the estrogen-induced alterations that give rise to the cancerous phenotype.

Green tea helps fights cancer?

Some subgroups of breast cancer are unresponsive to hormonal therapies, as they do not express estrogen receptors (ER^-). For effective SERM treatment, a re-activation of estrogen receptors was performed on ER^- MDA-MB-231 cells (a particularly aggressive breast cancer cell line). Expression of ER was altered with the addition of two dietary supplements: green tea polyphenols (GTPs) and sulforaphane (SFN). GTPs and SFN were shown to modulate epigenetic control of ER gene expression by altering DNA methylation and acetylation (respectively). SERM treatment was effective following ER up-regulation, thus providing evidence that GTPs and SFN supplements are capable of transforming ER^- breast cancer to a SERM-responsive form. GTPs and SFN have been know to possess anticarcinogenic properties, but these mechanisms are poorly understood in breast cancer models.

Finding cures for cancer has been difficult, as personalized treatments are required to address the heterogeneity of these diseases. By better understanding pathophysiology, we can identify potential therapeutic targets in the treatment of diseases.

I'm not saying green tea drinking pot heads have any sort of "protection" against cancer, but rather pointing out the varieties of therapies that provide a promising future in the treatment of breast cancer. The fight against breast cancer begins with awareness. Knowing symptoms of abnormalities can result in early detection of breast cancer, improving the chance of beating this disease. Check out Worldwide Breast Cancer website to enhance your awareness!

References:

Bifulco, M., A.M. Malfitano, S. Pisanti, C. Laezza. 2008. Endocannabinoids in endocrine and related tumours. Society for Endocrinology 15:391-408.

Bifulco, M., C. Laezza, S. Pisanti, P. Gazzerro. 2006. Cannabinoids and cancer: pros and cons of an antitumor strategy. British Journal of Pharmacology 148:123-135.

Caffarel, M.M., C. Andradas, E. Perez-Gomez, M. Guzman, C. Sanchez. 2012. Cannabinoids: A new hope for breast cancer therapy? Cancer Treatment Reviews 38:911-918.

Damiano, J.S., K.G. Rendahl, C. Karim, M.G. Embry, M. Ghoddusi, J. Holash, A. Fanidi, T.J. Abrams, J.A. Abraham. 2012. Neutralization of prolactin receptor function by monoclonal antibody LFA102, a novel potential therapeutic for treatment of breast cancer. Molecular Cancer Therapeutics [Epub ahead of print].

De Petrocellis, L., D. Melck, A. Palmisano, T. Bisogno, C. Laezza, M. Bifulco, V.D. Marzo. 1998. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. PNAS 95:8375-8380.

Goffin, V., S. Bernichtein, P. Touraine, P.A. Kelly. 2005. Development and potential clinical uses of human prolactin receptor antagonists. Endocrine Reviews (26)3:400-422.

Grimaldi, C., S. Pisanti, C. Laezza, A.M. Malfitano, A. Santoro, M. Vitale, M.G. Caruso, M. Notarnicola, I. Iacuzzo, G. Portella, V.D. Marzo, M. Bifulco. 2006. Anandamide inhibits adhesion and migration of breast cancer cells. Experimental Cell Research 312:363-373.

Guindon, J., A.G. Hohmann. 2011. The endocannabinoid system and cancer: therapeutic implication. British Journal of Pharmacology 163:1447-1463.

Jacobson, E.M., E.R. Hugo, D.C. Borcherding, N. Ben-Jonathan. 2011. Prolactin in breast and prostate cancer: molecular and genetic perspectives. Discovery Medicine (11)59:315-324.

Ohshiro, K., A.M. Schwarts, P.H. Levine, R. Kumar. 2012. Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling. PLoS ONE (7)1:1-8.

Leazza, C., A. D’Alessandro, S. Paladino, A.M. Malfitano, M.C. Proto, P. Gazzerro, S. Pisanti, A. Santoro, E. Ciaglia, M. Bifulco. 2012. Anandamide inhibits the Wnt/β-catenin signaling pathway in human breast cancer MDA MB 231 cells. European Journal of Cancer 48: 3112-3122.

Meeran, S.M., S.N. Patel, Y. Li, S. Shukla, T.O. Tollefsbol. 2012. Bioactive dietary supplements reactivate ER expression in ER-negative breast cancer cells by active chromatin modifications. PLoS ONE (7)5:1-14.

Preet, A., Z. Qamri, M.W. Nasser, A. Prasad, K. Shilo, X. Zou, J.E. Groopman, R.K. Ganju. 2011. Cannabinoid receptors, CB1 and CB2, as novel targets for inhibition of non-small cell lung cancer growth and metastasis. Cancer Prevention Research 4(1):65-75.

Van Dross, R., E. Soliman, S. Jha, T. Johnson, S. Mukhopadhyay. 2012. Receptor-dependent and receptor-independent endocannabinoid signaling: a therapeutic target for regulation of cancer growth. Life Sci 12:13469-13473.

Image references:

http://www.worldwidebreastcancer.com

http://mashable.com/2012/10/26/rethink-breast-cancers-app/