Background: Breast cancer (BC) is a very heterogeneous disease. Currently, decision-making regarding treatment of individual patients is based on several factors, most important of them are expression of estrogen receptors (ER), progesterone receptors and receptor for epidermal growth factor 2 (HER2). Common endocrine therapies include selective estrogen receptor modulator tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degrader fulvestrant. Inhibitors of cyclin dependent kinases 4/6 (iCDK 4/6) in combination with AIs or fulvestrant, are recently being used in treatment of metastatic BC. Trastuzumab, an anti-HER2 monoclonal antibody, is a cornerstone treatment in HER2 positive disease. Next to other chemotherapeutic drugs, cisplatin is commonly used in triple-negative BC. Cannabinoids, a therapeutic option in the palliative treatment of cancer patients, have recently been demonstrated to induce anti-tumor response in certain cancer types, including BC. Reportedly, cannabinoids have been shown to exert antiproliferative and antimetastatic activities against BC cells. The effects of cannabinoids on signaling pathways in cancer cells are conferred via G-protein coupled cannabinoid receptors (CBRs) type 1 (CB1) and type 2 (CB2), other receptors (e.g. GPR55, TRPV2) or in a receptor-independent way. Cannabidiol (CBD) is a ligand of CB1 and CB2 receptors and is not psychoactive. Recent studies have shown that TAM acts as inverse agonist on CBRs but the significance of this interaction is unknown.
Objectives: The aim of the study was to evaluate the effect of CBD on cell viability of selected BC cell lines of different subtypes (ER+, HER2+, triple-negative) alone and in combination with different BC therapies (TAM, fulvestrant, fulvestrant + iCDK 4/6, trastuzumab and cisplatin).
Methods: The expression of CBRs in BC cell lines (MCF7, MDA-MB-231, MDA-MB-361, T-47D, SK-BR-3) was confirmed using western blot (WB). We used polyclonal antibodies against CB1 and CB2 receptors (ab23703 and ab45942, Abcam), and were among the first to test the monoclonal antibodies (sc-518035 and sc-293188, Santa Cruz Biotechnology) that exhibit lower levels of the requested specificity. All tested cell lines (T-47D, MDA-MB-231, SK-BR-3) were exposed to different concentrations of CBD. In addition, T47D cell line (ER+) was exposed to combination of CBD and endocrine therapy (TAM, fulvestrant), as well as combination of fulvestrant and palbociclib. Triple-negative MB-231 cell line was exposed to combination of CBD and cisplatin and SK-BR-3 cell line (HER2+) to CBD and trastuzumab.
Results and Conclusions: CB1 and CB2 receptors are expressed in all tested BC cell lines. CBD decreased cell viability of all tested cell lines, however in MB-MDA-231 and SK-BR-3 cell lines only in above 25 µM concentrations. We are first to demonstrate that CBD increases the potency of TAM in inhibiting T-47D cell line viability. So far we could not confirm similar effect of CBD in combination with cisplatin, trastuzumab, fulvestrant alone or the combination of fulvestrant and iCDK 4/6.
Citation Format: Luka Dobovišek, Metka Novak, Fran Krstanović, Polonca Ferk, Simona Borštnar, Tamara Lah Turnšek, Nataša Debeljak. Cannabidiol increases potency of tamoxifen in inhibiting breast cancer cell viability [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-11.