Overview of Research on Cannabis for Breast Cancer

The earliest scientific research on the effects of cannabinoids on cancer cells date back to the mid-1970s, with Louis Harris’ investigations of tetrahydrocannabinol's (THC) inhibition of cancer growth (1,2). Research on cannabis as a potential treatment specifically for breast cancer didn’t begin for another 20 years, until the 1990s. Since then, there have been several thousand preclinical studies, most of which have been conducted only within the last 10 years. Scientific research on breast cancer is thus still in its early stages. What have we learned about cannabis to treat breast cancer? Let’s take a look.

Breast Cancer Is Diverse

Breast cancer tumors are extremely heterogeneous in nature, as noted by Rahman and colleagues (3): “Breast cancer shows intra-tumor heterogeneity at molecular, genomic and phenotypic levels.” One aspect of this diversity is tumor cells’ different patterns of expression of both hormone receptors and cannabinoid receptors.

Stratified Based on Receptor Status

The most reliable way of stratifying different breast cancer types is that based on hormone receptor expression, that is, whether or not the tumors contain estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (HER-2). The presence of any of these hormone receptors provides a target or pathway by which to attack the cancer (see Table I, click to enlarge) (3).

Breast cancer tumors that express hormone receptors (Luminal A, Luminal B, or HER-2+) may be treated using hormone therapy, which interferes with the body’s own production and effects of these hormones on promoting tumors. However, breast cancer tumors that do not express hormone receptors (triple negative breast cancer, or TNBC) do not respond to hormone therapy. Other treatment options for all breast cancer types include chemotherapy (oral or IV administration of drugs to stop cancer cell growth) or radiation therapy (4).

Cannabis Has Diverse Effects on Breast Cancer

Cannabis has been found to “selectively and differentially affect” different types of breast cancer cells (5). This is due to a combination of factors. First, the patterns in which cannabinoid receptors (CB1 and CB2) are expressed on tumors differ across cancer cell types (3,5). Next, CB2 receptors are more prevalent than CB1 receptors: CB1 is detected in 28% of breast cancer carcinomas, while CB2 is detected in 72% of carcinomas, where both CB1 and CB2 are found more often in HER-2 positive tumors (3). Finally, different cannabinoids that bind to the same type of receptor can cause different downstream effects on cancer cells. This phenomenon is known as biased signaling (6).

Research on Cannabis Use for Breast Cancer

There is a large body of preclinical and clinical research that includes all three forms of cannabinoids: endocannabinoids (made by the body), phytocannabinoids (made by plants), and synthetic cannabinoids (man-made). The research examines how cannabinoids may be used to treat cancer in general, as well as to treat specific forms of cancer, such as astrocytoma, glioblastoma, head and neck, breast, Hodgkin lymphoma, leukemia, skin, and squamous cell cancer. The research reported herein is focused specifically on studies of cannabinoid treatments for breast cancer.

Cannabis has been found to provide relief to breast cancer patients in three different ways: (i) cannabis addresses the symptoms associated with either the cancer itself or the side effects from cancer medications; (ii) cannabis increases the efficacy of complementary cancer treatments; and (iii) cannabis attacks the cancer itself. At the same time, however, a few studies have, in fact, found that cancer may promote tumor growth in breast cancer cells. Let’s take a closer look at what the studies have to say for each of these types of effects of cannabis on breast cancer.

Addresses Symptoms and Side Effects of Treatment

The list of side effects associated with cancer and cancer treatments is lengthy. Commonly reported side effects include, among others, pain, anxiety, depression, fatigue, insomnia, nausea or vomiting, and weight problems (7). There is a large body of research supporting the efficacy of cannabis for use in treating most of these symptoms and side effects of breast cancer.

Surveys

Surveys of patients with breast cancer indicate that a significant portion of patients (42% in one study) have used cannabis to treat their symptoms. These patients tend to find cannabis provides relief for most symptoms or side effects, including insomnia; joint and muscle aches, discomfort, stiffness, or pain; anxiety, stress; and nausea or vomiting (8,9).

Clinical Trials

No clinical trials have yet been performed to assess cannabis’s efficacy for treating symptoms and side effects specifically of breast cancer. However, many clinical trials of generic “cannabis,” as well as of specific cannabinoids have been tested and shown to be efficacious for treating symptoms generally associated with cancer and cancer treatment, including nausea or vomiting, pain, appetite, fatigue, anxiety, and depression. Notably, three of the four cannabis pharmaceuticals that have been government-approved—Dronabinol (1986 in US), Nabilone (1981 in Canada, 1985 in US), and Sativex (2010 in UK)—were approved to treat cancer-related symptoms and side effects. [Note: The fourth cannabinoid pharmaceutical approved for medical use is Epidiolex, approved by the FDA in 2018 for the treatment of epilepsy.]

Increases Effectiveness of Traditional Treatments

In preclinical studies, researchers have shown that cannabinoids enhance the anti-cancer effects of various other chemotherapy treatments in breast cancer cells (10), as well as in other cancer cell types (11).

Treats Breast Cancer

Scientists have discovered multiple pathways for preventing the growth and spread of breast cancer cells. Preclinical studies have well-established the potential for cannabis to address most of these pathways. Yet, while there are case reports, there have not yet been any clinical studies on cannabis for preventing the growth or spread specifically of breast cancer.

Preclinical studies on breast cancer cell lines have established the following findings.

Induces Cell Cycle Arrest

Caffarel and colleagues provide a succinct description of cell cycle arrest, together with cannabis’s role in managing the process when it goes awry (12): "There are very few critical decisions that cells must take during their lifetime. Basically, these are whether to proliferate, differentiate, or die. A tight regulation of the cell cycle is crucial to control all these decisions, and its deregulation has devastating consequences, such as cancer. It has been proposed that cannabinoids, the active components of Cannabis sativa, play a role in the control of the aforementioned decisions. For example, they can modulate survival, proliferation, and differentiation depending on the cell type and its physiopathologic context."

Inhibits Proliferation

Cell proliferation is the speed at which cancer cells replicate themselves. “If the cancer cells are dividing more rapidly, it means the cancer is faster growing or more aggressive” (13). There is a substantial body of preclinical research establishing that endo-, phyto-, and synthetic cannabinoids inhibit the proliferation of breast cancer tumors with cell types ER+ (11,14), HER-2+ (15,16), and TNBC (15,17).

Induces Apoptosis

Apoptosis is a natural process used by the body to rid itself of unneeded or abnormal cells (19). As with cell proliferation, there is also a substantial body of preclinical research establishing that endo-, phyto-, and synthetic cannabinoids promote apoptosis in breast cancer tumors with cell types ER+ (12,21), HER-2+ (12), and TNBC (21-22).

Blocks Angiogenesis

Tumors release chemicals that induce angiogenesis—the formation of new blood vessels—through which tumors draw their resources (23). Several preclinical studies show that endo- and synthetic cannabinoids block angiogenesis in TNBC (24,25).

Blocks Invasion, Metastasis, and Migration

Cancer cells spread from one location in the body to another using a specific process, called metastasis (26): “The process of tumour-cell invasion and metastasis is conventionally understood as the migration of individual cells that detach from the primary tumour, enter lymphatic vessels or the bloodstream and seed in distant organs.” There is a substantial body of preclinical research establishing that endo-, phyto-, and synthetic cannabinoids inhibit invasion, metastasis, and migration in breast cancer tumors with cell types ER+ (6,18), HER-2+ (3,6,14,16), and TNBC (3,6,14,16).

Promotes Breast Cancer Growth

Despite a wealth of studies supporting the breast cancer-fighting effects of cannabis, there are two studies that have shown that cannabis may actually promote tumor growth in breast cancer cells. Noteworthy is the fact that in both of those cases, the researchers indicated that the breast cancer cells that were examined expressed “low to undetectable levels of cannabinoid receptors” (20,29). The lack of cannabinoid receptors could thus be used as a marker for cases in which cannabis should not be used for cancer therapy.

Breast Cancer Markers for Cannabinoid Treatment

So, what we have is that breast cancer is diverse and may be classified based on the types of receptors the breast cancer cells express. In particular, a large portion of breast cancer cells have cannabinoid receptors and should thus react to cannabis. Indeed, surveys of breast cancer patients indicate that a significant portion of patients uses cannabis to relive symptoms, and clinical studies establish the efficacy of cannabis to treat the symptoms of cancer in general as well the side effects of cancer treatments. While clinical evidence assessing the benefits of cannabis for treating breast cancer have not yet been conducted, there is a large body of preclinical research establishing a theoretical basis for using cannabis, not only to treat the symptoms of breast cancer, but also to attack the cancer itself. Yet, there is reason for caution, as a few studies have shown that cannabinoids may, in fact, promote the growth of breast cancer cells.

So, then, what we need is a good marker not only for determining when cannabinoids should be considered as a treatment for breast cancer, given cannabis’s anti-cancer potential, but also for determining when cannabinoids should not be considered for treatment, due to its pro-cancer potential.

Researchers have shown that:

• Cannabinoid receptors (CBRs) are not expressed in non-tumor breast tissue (12,32).
• Cancer cells that have higher CBR expression tend to be more aggressive (11,12,15,31,32), as well as more responsive to cannabis (29,31,32).
• Cancer cells that have lower CBR expression tend to be either less responsive to cannabis (12) or even stimulated by cannabis (11,29,30).
• Cannabinoids may suppress immune system functioning (31).

Taken together, researchers have concluded that when CBR expression is low, then the negative effects of cannabinoids on inhibiting other immune responses to cancer growth outweighs any tumor-suppressing effects cannabinoids might have (30,31). Clearly, then, when CBR expression on breast cancer tumors is low, cannabinoids should not be considered as an anti-cancer therapeutic.

If, on the other hand, CBR expression on breast cancer tumors is high, then the beneficial effects of cannabinoids on suppressing tumor activity outweigh their negative effects on suppressing immune system activity (30,31). So, then when CBR expression on breast cancer tumors is high, cannabinoids should be considered as an anti-cancer therapeutic.

References

(1) L. Harris, A. Munson, M. Friedman,. et al, "Retardation of tumor growth by D9-tetrahydrocannabinol," The Pharmacologist (1974).

(2) A. Munson, L. Harris, M. Friedman, W. Dewey, and R. Carchman, "Antineoplastic Activity of Cannabinoid," J. Natl. Cancer Inst. DOI: 10.1093/jnci/55.3.597. Retrieved from pubmed.ncbi.nlm.nih.gov/1159836/ (1975).

(3) S. Rahman, et al, "The onus of cannabinoids in interrupting the molecular odyssey of breast cancer: A critical perspective on UPRER and beyond," (2019). Saudi Pharmaceutical Journal. DOI: 10.1016/j.jsps.2019.01.005 Retrieved from www.sciencedirect.com/science/article/pii/S1319016419300064 (2019).

(4) Breast Cancer Treatment (Adult) (PDQ®)–Patient Version. (2021, Apr 8) National Cancer Institute. Retrieved from www.cancer.gov/types/breast/patient/breast-treatment-pdq.

(5) L. Baram, E. Peled, P. Berman, B. Yellin, E. Besser, M. Benami, I. Louria-Hayon, G. Lewitus, and D. Meiri, "The heterogeneity and complexity of Cannabis extracts as antitumor agents," Oncotarget. DOI: 10.1016/j.jsps.2019.01.005. Retrieved from www.semanticscholar.org/paper/The-heterogeneity-and-complexity-of-Cannabis-as-Baram-Peled/ca3a543b372e5474439fbfc4bd5cbc4f41e904cf (2019).

(6) J. Glogauer and J. Blay, "Cannabinoids, Their Cellular Receptors, and Effects on the Invasive Phenotype of Carcinoma and Metastasis" Cancer Reports. DOI: 10.1002/cnr2.1475. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842690/ (2021).

(7) Treatment Side Effects (2021, Mar 29). Breastcancer.org. Retrieved from www.breastcancer.org/treatment/side_effects.

(8) J. Aviram, et al, "Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients," Pharmaceuticals. DOI: 10.3390/ph13120435. Retrieved from www.researchgate.net/publication/346484148 (2020).

(9) M. Weiss, et al "A survey of cannabis use for symptom palliation in breast cancer patients by age and stage," J. of Clinical Oncology. Retrieved from https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.12108 (2020).

(10) A.I. Fraguas-Sánchez, A. Fernández-Carballido, R. Simancas-Herbada, C. Martin- Sabroso, and A.I. Torres-Suárez, "CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer," International Journal of Pharmaceutics. DOI: 10.1016/j.ijpharm.2019.118916. Retrieved from pubmed.ncbi.nlm.nih.gov/31811927/ (2019).

(11) M.M. Caffarel, C. Andradas, E. Pérez-Gómez, M. Guzmán, and C. Sánchez, "Cannabinoids: A new hope for breast cancer therapy?" Cancer Treatment Reviews. DOI: 10.1016/j.ctrv.2012.06.005. Retrieved from www.semanticscholar.org/paper/Cannabinoids%3A-a-new-hope-for-breast-cancer-therapy-Caffarel-Andradas/998e07defe9c75215c34acae8118718f0e5bf55f (2012).

(12) M. Caffarel, et al, "D9-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation," Cancer Research. DOI: 10.1158/0008-5472.CAN-05-4566. Retrieved from cancerres.aacrjournals.org/content/canres/66/13/6615.full.pdf (2006).

(13) Breast Cancer Ploidy and Cell Proliferation. (2019, Sep 20) American Cancer Society. Retrieved from www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/ploidy-and-cell-proliferation.html.

(14) L. Dobovišek, et al, "Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment," Cancers. DOI: 10.3390/cancers12030525. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139952/pdf/cancers-12-00525.pdf (2020).

(15) D. Ladin, et al, "Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents," Frontiers in Pharmacology. DOI: 10.3389/fphar.2016.00361. Retrieved from www.ncbi.nlm.nih.gov/pmc/articles/PMC5054289/pdf/fphar-07-00361.pdf (2016).

(16) M. Elbaz, et al, "Modulation of the Tumor Microenvironment and Inhibition of EGF/EGFR Pathway; Novel Anti-tumor Mechanisms Of Cannabidiol In Breast Cancer," Molecular Oncology. DOI: 10.1016/j.molonc.2014.12.010. Retrieved from www.meta.org/papers/modulation-of-the-tumor-microenvironment-and/25660577 (2015).

(17) R. Murase, et al, "Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer," British J. of Pharmacology. DOI:10.1111/bph.12803. Retrieved from pubmed.ncbi.nlm.nih.gov/24910342/ (2014).

(18) Apoptosis. (n.d.) National Cancer Institute. Retrieved from
www.cancer.gov/publications/dictionaries/cancer-terms/def/apoptosis.

(19) A. Tomko, et al, "Antitumor Activity of Abnormal Cannabidiol and Its Analog O-1602 in Taxol-Resistant Preclinical Models of Breast Cancer," Frontiers in Pharmacology. DOI: 10.3389/fphar.2019.01124. Retrieved from www.frontiersin.org/articles/10.3389/fphar.2019.01124/full (2019).

(20) A. Sultan, M. Marie, and S. Sheweita, "Novel mechanism of cannabidiol-induced apoptosis in breast cancer cell lines," The Breast. DOI: 10.1016/j.breast.2018.06.009. Retrieved from pubmed.ncbi.nlm.nih.gov/30007266/ (2018).

(21) A. Shrivastava, et al, "Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy," Mol. Cancer Ther. DOI: 10.1158/1535-7163.MCT-10-1100. Retrieved from pubmed.ncbi.nlm.nih.gov/21566064/ (2011).

(22) Angiogenesis. (n.d.)National Cancer Institute. Retrieved from
www.cancer.gov/publications/dictionaries/cancer-terms/def/angiogenesis.

(23) P. Picardi, E. Ciaglia, M. Proto, and S. Pisanti, "Anandamide inhibits breast tumor-induced angiogenesis," Transl. Med. UniSa. Retrieved from elea.unisa.it/jspui/bitstream/10556/1634/1/Picardi_Ciaglia_Proto_Pisanti_Anandamide_inhibits_breast_tumor_induced_angiogenesis.pdf (2014).

(24) N. Farsandaj, M. Ghahremani, and S. Ostad, "Role of cannabinoid and vanilloid receptors in invasion of human breast carcinoma cells," J. Environ. Pathol. Toxicol. Oncol. DOI: 10.1615/jenvironpatholtoxicoloncol.2013005859. Retrieved from pubmed.ncbi.nlm.nih.gov/23394450/ (2012).

(25) P. Friedl and K. Wolf, "Tumour-cell invasion and migration: diversity and escape mechanisms," Nature Reviews Cancer. Retrieved from www.nature.com/articles/nrc1075/briefing/signup/ (2003).

(26) S. Takeda, et al, "Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration," Toxicology Letters. DOI: 10.1016/j.toxlet.2012.08.029. Retrieved from pubmed.ncbi.nlm.nih.gov/22963825/ (2012).

(27) S. Takeda, et al, "D9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling," Toxicology. DOI: 10.1016/j.tox.2007.12.019. Retrieved from www.sciencedirect.com/science/article/abs/pii/S0300483X07008566 (2008).

(28) R. McKallip, M. Nagarkatti, and P. Nagarkatti, "∆-9-Tetrahydrocannabinol Enhances Breast Cancer Growth and Metastasis by Suppression of the Antitumor Immune Response," J. Immunol. DOI: 10.4049/jimmunol.174.6.3281. Retrieved from www.jimmunol.org/content/174/6/3281 (2005).

(29) B. Dariš, M. Verboten, Z. Knez, and P. Ferk, "Cannabinoids in cancer treatment: Therapeutic potential and legislation," Bosnian J. of Basic Medical Sciences. DOI: 10.17305/bjbms.2018.3532. Retrieved from www.ncbi.nlm.nih.gov/pmc/articles/PMC6387667/pdf/BJBMS-19-14.pdf (2018).

(30) T. Kisková, et al, Retrieved from Future Aspects for Cannabinoids in Breast Cancer Therapy. International J of Molecular Sciences. DOI: 10.3390/ijms20071673. Retrieved from www.ncbi.nlm.nih.gov/pmc/articles/PMC6479799/pdf/ijms-20-01673.pdf (2019).

About the Author

Ruth Fisher, PhD, is a systems design researcher and analyst. She analyzes markets to determine how environments shape outcomes. She is co-founder of CannDynamics, Inc., and author of The Medical Cannabis Primer and Winning the Hardware-Software Game: Using Game Theory to Optimize the Pace of New Technology Adoption. Dr. Fisher has worked in the technology and healthcare sectors on behalf of technology companies, early-stage researchers, physicians, and technology start-ups.