Study Finds Low-Dose THC Reduces Breast Cancer Aggressiveness, Improves Tamoxifen Sensitivity in Tumor Models
- Brief exposure to low doses of THC pushes breast cancer cells into a less aggressive, more mature "luminal-like" state, reducing their invasiveness, self-renewal, and tumor-initiating capacity.
- The effects are largely mediated by cannabinoid receptor 2 (CB2R), with selective CB2R targeting compounds producing similar long-lasting changes in tumor cell behavior.
- THC treatment increases cancer cells’ sensitivity to the drug tamoxifen and limits the development of treatment resistance, with effects persisting even under conditions promoting aggressive cancer traits.
- Animal studies and genetic analyses confirm that transient CB2R modulation causes sustained changes in cancer cell identity, suggesting a novel differentiation-based therapy to limit tumor progression and plasticity.
A new study finds that brief exposure to low doses of THC can push breast cancer cells toward a less aggressive state, reducing their ability to invade, self-renew and initiate new tumors while making them more responsive to the breast cancer drug tamoxifen.
The peer-reviewed study, published in the journal Communications Biology, examined whether temporarily manipulating cannabinoid receptor 2 (CB2R) could produce lasting changes in breast cancer cells rather than simply killing them. Researchers used three-dimensional tumor organoids derived from both human patient samples and mouse breast tumors.
Cancer cells can exhibit what researchers call plasticity, allowing them to shift between more differentiated states and stem-like states. This flexibility can contribute to tumor progression, metastasis and treatment resistance. Researchers exposed the tumor organoids to low doses of delta-9 tetrahydrocannabinol (THC) for four days before removing the compound.
Rather than returning to their previous state once THC was removed, the treated cells remained stabilized in a more mature, “luminal-like” state. They displayed lower levels of self-renewal and invasiveness and a reduced capacity to initiate tumors.
The researchers found that the effects appeared to be driven largely by CB2R rather than cannabinoid receptor 1 (CB1R). A separate compound selectively targeting CB2R produced similar long-lasting effects, strengthening evidence that the receptor itself was responsible for the changes.
The treatment also increased the cancer cells’ sensitivity to tamoxifen and limited the development of treatment-resistant characteristics. According to the study, the effects remained even when cells were exposed to conditions designed to encourage them to return to a more stem-like and aggressive state, including immune signaling, mechanical stress, stromal co-culture and transforming growth factor beta exposure.
The researchers also examined the approach in animals by transplanting treated tumor cells into mice. According to study coauthor María Salazar-Roa, the effects persisted in vivo for more than 100 days after the cannabinoid treatment had been withdrawn.
“The drug was gone, but the phenotype remained,” Salazar-Roa wrote in a discussion of the findings.
Genetic and epigenetic analyses provided additional evidence that the treatment was producing a sustained change in cellular identity. RNA sequencing showed a progression from a more plastic state toward a stabilized luminal-like state, while chromatin analysis identified remodeling associated with that transition.
The researcher say the results point to CB2R as a potentially important regulator of cancer cell identity and suggest that short-term cannabinoid receptor modulation could provide a new approach to limiting the cellular plasticity that contributes to tumor progression and treatment resistance.
“Our findings redefine CB2R as a regulator of tumor cell state and establish transient CB2R modulation as a strategy to durably constrain breast cancer plasticity through differentiation-based therapy,” researchers conclude.