Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


DISSERTATION final 3.pdf (2.92 MB)

ETD Abstract Container

Abstract Header

The Role of Cannabinoids and their Receptors in Breast Cancer

Elbaz, Mohamad Mostafa Abdelhamid
http://rave.ohiolink.edu/etdc/view?acc_num=osu1457000596

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Breast cancer is a heterogeneous disease that has different biological and clinical behaviors. It represents the second cause of cancer deaths among US women. Cannabinoids can be classified into endocannabinoids, synthetic cannabinoids and phytocannabinoids. These cannabinoids act on different receptors such as Cannabinoid receptor-1 (CB1R), Cannabinoid receptor-2 (CB2R), Transient receptor potential vanilloid type-2 (TRPV2). In this thesis, we examined the anti-tumor role of an important phytocannabinoid, Cannabidiol (CBD), and a specific CB2R agonist synthetic cannabinoid, JWH-015. We also studied the role of CB2R activation in cancer cells as well as immune cells and finally we analyzed TRPV2 role in improving the efficacy of chemotherapeutic drugs. Our study shows that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibition EGF/EGFR signaling and modulating the tumor microenvironment (TME). We also found that TRPV2 is significantly up-regulated in primary and metastatic breast cancer compared to normal breast tissues. We also observed that TNBC patients with higher TRPV2 expression and committed to chemotherapy have significantly higher recurrence free survival compared to patients with lower TRPV2 expression. We also showed that TRPV2 overexpression significantly increased doxorubicin (DOX) uptake and efficacy. We showed that TNBC cells that are subjected to combination treatment (CBD+DOX) have less viability compared to DOX-treated cells. Analysis of molecular mechanisms showed higher levels of cleaved PARP and caspase-3 in combination treatment compared to DOX alone. Further studies, revealed that CBD enhanced the uptake of DOX into TNBC cells. Importantly, we show that CBD effects are TRPV2-mediated and TRPV2 downregulation or interference by its dominant negative form inhibits DOX-mediated cytotoxicity. In vivo studies showed that (CBD+DOX)-treated mice have significantly reduced tumor weight and enhanced cleaved (caspase-3/PARP) levels compared to DOX group. Our studies showed that CB2R specific agonist (JWH-015) inhibited EGF and IGF-I-induced migration and invasion of ERa+ and ERa- breast cancer cells. At the molecular level, JWH-015 inhibited EGFR and IGF-IR activation and their downstream targets STAT3, AKT, ERK, NF-kB and MMP-9/MMP-2. Interestingly, we found that JWH-015 significantly reduced breast cancer growth in vivo and the tumors derived from CB2R agonist treated mice showed reduced activation of EGFR and IGF-IR and their downstream targets. Since CB2R is highly expressed in immune cells, we assessed CB2R role on modulation of immune cells present in tumor stroma. We observed increased tumor weight, more myeloid derived suppressor cells (MDSCs) (CD11b+/Gr-1+) and less CD3+/CD8+ cells in orthotopically injected CB2R knock out mice compared to wild type mice. Furthermore, we found that JWH-015-treated wild type mice had reduced tumor growth and metastasis, more CD3+/CD8+ cells and less MDSCs within the tumor stroma. Overall, our studies showed that CBD and JWH-015 exert strong anti-tumor activities against breast cancer. They both inhibit hallmark signaling pathways. In addition, these drugs have TME modulating potential through different mechanisms which eventually enhance the anti-tumor immunity against breast cancer cells. Finally, we show that CBD, upon activating TRPV2 channel, increases the uptake capacity of breast cancer cells and makes these cancer cells more susceptible to the anti-tumor chemotherapeutic drugs.
Ramesh Ganju (Advisor)
Sujit Basu (Committee Member)
Kalpana Ghoshal (Committee Member)
Xue-Feng Bai (Committee Member)
193 p.
Biology; Health Sciences
Breast cancer , CBD, JWH-015

Recommended Citations

Citations

  • Elbaz, M. M. A. (2016). The Role of Cannabinoids and their Receptors in Breast Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1457000596

    APA Style (7th edition)

  • Elbaz, Mohamad Mostafa Abdelhamid. The Role of Cannabinoids and their Receptors in Breast Cancer. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1457000596.

    MLA Style (8th edition)

  • Elbaz, Mohamad Mostafa Abdelhamid. "The Role of Cannabinoids and their Receptors in Breast Cancer." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1457000596

    Chicago Manual of Style (17th edition)

osu1457000596
717
© 2016, some rights reserved.Creative Commons License The Role of Cannabinoids and their Receptors in Breast Cancer by Mohamad Mostafa Abdelhamid Elbaz is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.