Breast cancer includes multiple subtypes, not just TNBC (triple-negative) and MCF-7 variants, but others as well. Although certain cannabinoids and terpenes may be beneficial, a few might potentially worsen some subtypes. The following overview outlines which cannabinoids and terpenes could help and highlights situations where caution is advised.

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Potentially Helpful Cannabinoids: CBD and THC for some subtypes. CBD only for triple-negative breast cancer subtype MDA-MB-231, and the MCF-7 subtype co-expressing Aromatase and COX-2 (where THC might exacerbate growth). (56F)

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Potentially helpful terpenes: Limonene, β-Caryophyllene, Humulene, Isocaryophyllene appear beneficial across multiple breast cancer models. (57F,58F)

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Terpenes that target NF-κB: α-Pinene, Humulene, α-Phellandrene, Geraniol, Cedrol, Thymol may help inhibit NF-κB, thus providing anti-inflammatory or anti-proliferative effects.(12C 10D 38D 49D 84D 6E 25E)

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Terpenes to avoid (preliminary): Eucalyptol is a TRPM8 agonist, (33D) it could worsen breast cancers overexpressing TRPM8. Further research is needed to confirm or refute this risk.

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MCF-7    

 

 

     MCF-7 cancer cells respond and grow from estrogen, as demonstrated by induction of known estrogen target mRNAs following exposure to 17β-estradiol. (59F)

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Potential Pharmacological Targets

 

 

TRPM7

 

     Overexpressed in MCF-7 cells; antagonizing TRPM7 may reduce metastasis. (60F) Carvacrol, a terpene found in oregano, is a known TRPM7 inhibitor. (18E)

 

TRPV1

 

     A study suggests that low-dose activation of TRPV1 (e.g., with capsaicin) can induce apoptosis in tumor cells, whereas higher doses may trigger necrosis. (60F)

 

TRPM8

 

     In low-aggressive MCF-7 subtypes that overexpress TRPM8, the channel promotes Epithelial–Mesenchymal Transition (EMT), which is a process marked by loss of cell adhesion and increased cell motility, central to metastasis. (60F)

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Terpenes tested against MCF-7 Breast Cancer Cell Line

 

Alpha-humulene inhibited MCF-7 by 50% (87C)

 

Isocaryophyllene inhibited MCF-7 by 69% (87C)

 

Beta-Caryophyllene with a-humulene inhibited MCF-7 by 75% (87C)

 

Beta-Caryophyllene with Isocaryophyllene inhibited MCF-7 by 90% (87C)

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THC can worsen a subtype of MCF-7 breast cancer

 

THC has anti-cancer effects for some breast cancer cell lines

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EVSA-T cells - THC induced apoptosis (56F)

 

MCF-7 - THC decreased cell proliferation (56F)

 

MCF-7 aro cells - THC induced apoptosis; reduction in aromatase and ERα protein levels (56F)

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MCF-7 Subtype that should avoid THC

 

There is a subtype of the MCF-7 cell line that is sensitive to 17β-estradiol (E2), and co-expresses COX‑2 and aromatase. (61F)

 

     The proliferation caused by THC involves both COX-2 and aromatase. Arachidonic acid, a COX substrate, enhances THC-induced growth. Δ(9)-THC–induced proliferation is blocked by COX-2 inhibitors. (61F)

 

     Aromatase inhibitors can worsen THC-induced proliferation. Testosterone is an aromatase substrate, and externally added E2 interfere with Δ(9)-THC’s proliferative effect. COX-2 inhibitors, arachidonic acid, and PGE2 do not alter aromatase expression. This indicates that COX-2 and aromatase act separately in THC-driven proliferation. (61F)

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With TRPM8 overexpresed MCF-7 subtype, would we need TRPM8 agonists or antagonists?

 

     We do know that another type of breast cancer, Triple Negative Breast Cancer subtype MDA-MB-231, had decreased cell migration and invasion using TRPM8 antagonists. (60F) It is not known how a TRPM8 agonist would work in this case, either by making the cancer worse or by desensitizing and downregulating the overexpressed TRPM8 receptors.

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TRPM8 agonist: eucalyptol (1,8 cineole). 33D Eucalyptol probably should be avoided until research shows what an agonist does with this subtype of cancer.

 

Cannabinoids that are TRPM8 antagonists: CBC, CBG, CBD, CBN, THC, THCA, THCV, CBDV, CBDA, THCVA, CBGV (3A,19A,54A)

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Terpenes in Three Additional Cancer Models: DLD-1, L-929, and MDA-MB-213

 

DLD-1

 

     Beta-Caryophyllene enhances the anticancer effects of alpha-humulene, isocaryophyllene and paclitaxel against the DLD-1 cancer cell line. (87C)

 

L-929

 

    Beta-Caryophyllene enhances the anticancer effects of alpha-humulene, isocaryophyllene and paclitaxel against the L-929 cancer cell line. (87C)

 

MDA-MB-213

 

     TRPM7 is overexpressed in MDA-MB-213 cells. Antagonizing TRPM7 could help reduce metastasis in this cell line. (60F) The terpene carvacrol (found in oregano) is a TRPM7 inhibitor. (18E)

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Triple-Negative Breast Cancer (TNBC)

 

     TNBC is a very difficult cancer to treat. They do not have the typical receptors for pharmacological targets which are estrogen receptors, progesterone receptors, or large amounts of Human Epidermal Growth Factor Receptor 2 (HER2/neu) on the cell surface. (62F)

 

     TNBC has increased TRPV2 expression. Doxorubicin (Adriamycin) has improved uptake by the cancer cells when TRPV2 is activated, which is associated with better prognosis. (60F)

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CBD, THC, and TRPM8 study on the TNBC subtype MDA-MB-231

 

TRPM8 antagonists decreased cell migration and invasion in MDA-MB-231 cells. (60F)

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     CBD had antiproliferative and proapoptotic in MDA-MB-231 cells through CB1, CB2, TRPV1 receptors, and the signaling pathways AKT/mTOR, Raf/MEK/ERK, NF-κB, Id-1. (56F)

 

     In vivo, CBD showed tumor growth reduction, though resistance can occur. Reactive Oxygen Species (ROS) generation contributes to apoptosis, but TNBC cells can also exploit ROS for tumor progression, adding to the treatment problem. (56F)

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THC could make TNBC subtype MDA-MB-231 worse

 

     THC could worsen TNBC subtype MDA-MB-231, by promoting proliferation rather than inhibiting it. (56F) There wasn't much more physiology available on the online journal about this.

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Trace cannabinoids with TNBC subtypes MCD-MB-231 and MDA-MB436

 

     CBG, CBN, CBN and CBG showed that they could reduce cancer cell viability and migration through decreasing in Id-1 expression (Inhibitor of DNA-binding 1). (56F)

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Terpenes that affect AKT/mTOR, Raf/MEK/ERK, NF-κB, Id-1, COX-2

 

     Since decreasing AKT/mTOR, Raf/MEK/ERK, NF-κB, Id-1 with CBD  has been shown to help with TNBC, (56F) we can possibly affect those pathways with terpenes to increase the effectiveness with CBD.

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NFkb

 

NFkb is reduced by alpha-pinene, humulene, eucalyptol, a-phellandrene, geraniol, cedrol, and thymol. (12C 10D 38D 49D 84D 6E 25E)

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Is eucalyptol bad for TNBC subtype MDA-MB-231

 

     Eucalyptol also is an agonist of TRPM8. (33D) In MDA-MB-231 cells, TRPM8 antagonists will decrease cell migration and invasion. (60F) Agonists typically act opposite of antagonists, which could increase cell migration and invasion by increasing ion flow into the cell. Until more research is available, eucalyptol should be avoided with MDA-MB-231 cancer.

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AKT/mTOR

 

     Limonene lowers p-Akt (Ser473) and p-Akt (Thr308). Other anti-cancer effects of limonene are reducing p-GSK-3β (Ser9), and activating caspase-3, caspase-9, and PARP. Bax protein and cytosol cytochrome c from mitochondria were increased, and bcl-2 protein was reduced. (97B)

 

     Carvacrol affects the cell signals PI3K/AKT/mTOR, MAPK, STAT3, and Notch. It also inhibits cell migration, invasion, and angiogenesis in tumor cells. (21E)

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COX-2

 

Breast cancer often overexpresses COX-2 (62F)

 

     Terpenes that interact with COX-2: (-)-α-bisabolol is a COX-2 modulator, (62D) geraniol is a COX-2 inhibitor, (77D) carvacrol is a COX-2 inhibitor, (18E) eugenol is a COX-2 modulator or expression inhibitor. (68E)

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CBD resistance

 

     Since TNBC subtype MDA-MB-231 can become resistant to CBD, (56F) adding a mix of terpenes could be helpful in overcoming that resistance. By using several terpenes, side effects could be reduced compared to taking a lot of one.

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Taxol-resistant breast cancer

 

Taxol-resistant MCF-7 are much more difficult to treat clinically. (63F) There are a few studies to show some different anti-cancer effects.

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Nerolidol and β-caryophyllene produced the greatest cytotoxic effects. (58F)

 

Combinations with the flavonoid kaempferol potentiated the cytotoxic effects of ocimene, terpinolene, and β-myrcene. (58F)

 

Combining nerolidol with Δ9-THC or CBD produced results ranging from antagonism to increased synergy.(58F)

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HER2+ breast cancer

 

     When Human Epidermal growth factor Receptor 2 (HER2) is overexpressed or amplified in breast cancer, excessive cancer growth and more aggressive tumor behavior occurs. Medications like trastuzumab block those signals and inhibit tumor growth. (64F)

 

     90% of HER2+ tumors have an overexpression of CB2, which is associated with a poor prognosis. CB1 is also expressed, but in lower amounts. THC was found to reduce tumor growth, angiogenesis and the formation of metastasis through the induction of apoptotic cell death and inhibition of AKT. (56F)

 

     This type of cancer would likely benefit by using CBD and THC to affect both of the CB1 and CB2 receptors. Beta-caryophyllene is a CB2 agonist. (72A)

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TRPV4 can worsen some breast cancer types

 

     Activating TRPV4 could potentially worsen breast cancer progression. (60F) It is not known if cannabinoids known to stimulate TRPV4 would actually aggravate the disease.

 

TRPV4 agonists include: CBDV, CBG, THCV, CBN, CBGV, CBGA (3A,54A)

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     Those cannabinoids are in very low quantities in cannabis, unless using a THCV or CBG strain. Some cannabinoids might modulate TRPV4 rather than fully activating it, which could regulate ion flow instead of flooding the cell with calcium. Not all TRPV4 agonists behave identically. For instance, THCV acts as a stimulant and can trigger palpitations in some users. CBN is sedative, with no known link to palpitations, even though both interact with TRPV4.

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     These cannabinoids also antagonize TRPM8, (3A,19A,54A) which is beneficial for some breast cancer types. It is not known if that would help counteract the TRPV4 agonism.

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     Since there are a lot of unknowns, these cannabinoids need to be researched for their effects on breast cancer, and if they increase cancer growth or not. It is better to stick with CBD, terpenes, and THC for certain breast cancer subtypes.

 

 

 

Limonene for treating breast cancer

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Study Overview

 

Type of Study: Open-label pilot clinical study with 43 women who had operable breast cancer and took 2 g of limonene daily for 2–6 weeks before surgery. (57F)

 

Goal: To measure how limonene and its metabolites distribute in breast tissue and to assess changes in biomarkers related to breast cancer risk. (57F)

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Tissue Distribution of Limonene

 

High Concentration in Breast Tissue: Limonene preferentially accumulated in breast tissue at a mean level of 41.3 μg/g. (57F)

 

Major Circulating Metabolite: Perillic acid, however, did not concentrate in the breast tissue, suggesting limonene itself is the primary compound reaching the tumor site. (57F)

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Effects on Tumor Biomarkers

 

Cyclin D1: A 22% reduction (p = 0.002) in tumor tissue, indicating potential suppression of cell cycle progression. (57F)

 

Ki67 and Cleaved Caspase-3: Minimal changes, so no clear effect on these proliferation/apoptosis markers. (57F)

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Systemic Biomarkers

 

     There was a slight increase in IGF-1 post-intervention, which is statistically significant, but the clinical significance is unclear. There were no significant changes in Leptin, adiponectin, TGF-β1, IGFBP-3, IL-6 remained essentially unchanged. (57F)

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Conclusions and Implications

 

     Limonene’s inhibition of cyclin D1 could lead to cell cycle arrest and reduced proliferation in breast tumor cells. Limonene shows promise as a chemopreventive or therapeutic agent, but more rigorous, placebo-controlled trials are needed to solidify its role in breast cancer prevention or treatment. (57F)

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How much cannabis oil is needed to treat cancer?

 

     There are no studies on the dose needed. The only thing we have is the story of Rick Simpson, who cured his own cancer (basal cell carcinoma) from topically applied cannabis oil. He advocated for people with cancer to eat 1 gram of cannabis oil per day, starting off small and working up to higher doses. Also to spread the doses throughout the day. There are plenty of images online showing the “Rick Simpson Oil Dosing”. He did use Indica for the higher THC, but that was in the 1990’s; before stronger strains were created. We don’t know the strain or terpene content.

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     Flooding the body with cannabinoids with such a high dose can have side effects, including nausea and vomiting. Keeping the body constantly fueled with cannabinoids would activate many TRP receptors on the immune cells active, allowing for better phagocytosis. Also, the cancer itself would be getting cannabinoids on their receptors, which could reduce the ions going into the cell, feeding the cancer.

 

     Not everyone can handle 1 gram of cannabis oil per day. Balancing that THC out with CBD would help with many symptoms. Using different strains together can also help reduce the symptoms. For example, I tried Lemon Kush which can cause extreme hunger, but is very nauseating with large doses. Mixing that with Jack Herer made the nausea go away, as well as the other side effects. I don’t have cancer, but use this for seizure reduction. Some people would need to use CBD and 1-2 THC strains to reduce side effects.

 

     One way to try and dose, is eat just enough cannabis oil so that there are minimal side effects and nausea. Repeating the dose after 3-6 hours, or when tolerated, can be done to keep the immune cells active. Doses can be increased slowly everyday to either 1 gram or what is tolerated.

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There is research on how much CBD is prescribed for some seizure types.

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     This can give us an idea on how much is used. Epidiolex (CBD) is prescribed for children that are at least 1 year old. It is not known what happens to children under 1 that take Epidiolex.(46F) The doses are as follows (taken from the Epidiolex insert):

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      “The recommended starting dosage is 2.5 mg/kg by mouth twice daily (5 mg/kg/day).  After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, EPIDIOLEX can be increased up to a maximum recommended maintenance dosage of 10 mg/kg twice daily (20 mg/kg/day).“ 10 and 20 mg/kg/day dosages may lead to elevated liver enzymes. (46F)

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     Possible side effects in patients with Lennox-Gastaut syndrome or Dravet syndrome are:  somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. (46F)    

 

     Possible side effects in patients with tuberous sclerosis complex are: diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting. (46F)

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TRPM8 in breast cancer

 

     TRPM8 is overexpressed in breast cancer, (65F) most notably in MCF-7. TRPM8 activation enhances autophagy through AMPK activation. (66F)

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     Cannabinoids are antagonists of TRPM8, which would seem like that could worsen cancer, but there are no reports of that. This could be from the cannabinoids interacting with other receptors that modulate TRPM8, or they act more like a partial antagonist than a full antagonist.

 

The terpene eucalyptol is a TRPM8 agonist, (33D) which could be helpful with breast cancer that over-expresses TRPM8.

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Delta 9 THC decreases 15-LOX in breast cancer

 

     Delta 9 THC is a direct inhibitor of 15-Lipoxygenase (15-LOX) with an IC(50) at 2.42 μM. The liver metabolite Delta 9 THC-11-oic acid is non-psychoactive, and also inhibits 15-LOX. (61F)

 

     Breast cancer expresses decreased levels of 15-LOX, and increased levels of 12-LOX and COX-2. (67F) 15-LOX inhibitors may be useful for the treatment of some cancers, and are being researched for that use. (68F) Further research is needed to look at the effects of COX-2 inhibition with cancers that express an increase in COX-2. There may also be a difference with how selective COX-2 inhibitors like Celebrex, and how non-selective COX-2 inhibitors that also affect COX-1 like ibuprofen may affect cancer. It is unknown if those anti-inflammatories could help with cancer treatment, or have unintended effects on the microenvironment of cancers that express high levels of COX-2.