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THC May Have Anti-Tumor Action Against HER2 Positive Breast Cancer

Branna Z.
woman's shirt with pink ribbon on it

HER2 positive proteins can form a compound with CB2 receptors that increases the deadliness of breast cancer. THC may stop that from happening.

Breast cancer is complex disease with numerous molecular markers, multiple treatments,  and variant prognoses. There is a subtype of breast cancer that is characterized by the overexpression of the human epidermal growth factor 2 (HER2). It represents 15-20% of all breast tumors and patients with this expression are said to be HER2 positive.

What Does it Mean to be HER2 Positive?

HER2 positive means that cancer grows by increasing the activity and number of proteins that control cell proliferation.  As a result, therapies target this overexpression of HER2. Currently, Trastuzumab, a recombinant humanized monoclonal anti-HER2 antibody, has significantly improved outcome for patients. However, despite its efficacy in many HER2 positive breast cancer cases, some patients do not respond to this treatment at all. Others eventually develop resistance to the drug. Therefore, there is a need for the alternate treatment to address this growing problem in the breast cancer patients.

women holding hands in pink shirts for breast cancer

Anti-Tumor Action of Cannabinoids

Cannabinoids produce anti-tumor responses in preclinical models of cancer, including HER2 positive breast cancer. In most cases, the anti-tumor responses are a result of the  binding and activating of cannabinoid receptors, CB1- and CB2 receptors. Preclinical research into HER2 positive tumors finds that CB2 is the main target for anti-tumor treatment.

A possible clue for the mechanism of turning HER2 on and off involves the formation of this double protein molecule, called a heterodimer. It forms between HER2 and CB2 receptor. Although the functional relevance of these heterodimers is still unknown, it has been  determined that the higher expression of the the heterodimers (HER2-CB2R), the less favorable the patient outcome. Higher expression of heterodimers was also observed in the metastatic tissue of the primary HER2 positive tumor.

Study Determines THC Can Target Heterodimers

A 2019 study was performed in vitro, analyzing several different HER2 positive breast cancer cell lines. It is already known that CB2 receptor activation for different models of the HER2+ breast cancer leads to the cancer cell death, by apoptosis. This also results in inhibition of: tumor growth, tumor blood vessel formation and metastasis.

HER2 positive cell lines were treated with THC in order to test the hypothesis. The results showed that THC definitely decreased the viability of these cancer cell lines in a concentration dependent manner. THC treatment diminished the amount of CB2R that joined with HER2, which points to the cannabinoid-induced disruption of the heterodimer.

Data showed that THC decreases the volume of these heterodimer complexes by activating the CB2 receptors. The findings conclude THC disrupts HER2-CB2R heterodimers, blocks HER2 activation and then also promotes its degradation. All of this adds up to a significant anti-tumor response.

breast cancer woman in tank top checking for lumps

To summarize, this study shows a mechanism controlling the activity of the HER2 that may represent a new target for anti-tumor treatments. Specifically, HER2 physically interacts with a membrane receptor (CB2) that doesn’t belong to the HER2 family. This interaction creates a CB2-HER2 heterodimer, which is associated with poor outcome for HER2 positive patients. THC inactivates this coupling process and degrades HER2, thus promoting anti-tumor action.

Since this study is performed in vitro, the possibility of the involvement of the other cell types cannot be neglected. For example, immune cells and endothelial cells also express CB2 receptors and it is reasonable to think that THC might also affect them. It would be interesting to see if the preclinical data could support the results demonstrated in this study.

Branislava Zagorac
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