Cannabinoids Reduce ErbB2-Driven Breast Cancer Progression Through Akt Inhibition

Published in Molecular Cancer, July 2010

Main Findings: THC-based medicine, when used as an experimental drug of treatment, significantly reduced breast cancer tumor growth, tumor numbers, induces cancer cell suicide (called apoptosis), and stopped the breast cancer cells from spreading to the lungs.

A very specially genetically bred mouse (MMTV-neu) that makes human-like breast tissue was used. This animal is the gold standard that is used and recognized in all breast cancer research because its genes have been changed and instructed to grow the same type of aggressive breast cancer tissue.

Also, these mice/clones are all identical to each other in every way, which allows for tight experimental controls. These mouse experiments speed up research, because humans are not involved, only their diseased tissue.

Advanced ErbB2 driven breast cancer typically spreads to the lungs and has a poor outcome for survival with existing conventional treatments used presently. A new, novel treatment idea was desperately needed to find a (non-toxic?) effective new medicine to be a game changer.

The ErbB2 receptor (stands for “human epidermal growth factor receptor 2”) is an “antenna” that sits on the outside of the breast cell. Its job is to pick up signals from hormones that instruct the cell to turn on a function inside the cell, such as keep growing and keep dividing. The ErbB2 gene behaves the same way in uterine and stomach cancer, and the same cannabinoid pathway could potentially be used.

Akt 1 is a gene found in breast cell DNA that keeps breast cells alive by instructing the cell to continue to make proteins inside itself. These proteins are the building blocks that allow the cell to keep building itself and keeps it alive by maintaining its structure.

Apoptosis is literally “programmed cell death.” As cells age and can no longer carry on their functions they are genetically programmed to die when they reach the end of their life cycle to make room for newer, younger cells. The Akt 1 gene blocks apoptosis — this programmed death signal — from turning on and promotes continued cell survival. If the Akt 1 gene’s functions can be blocked in a cell, that starts the “programmed cell death” command to be executed. If this happens in many cancer cells, the cancer tumor starts to shrink. The Akt 1 gene has been implicated as a major factor in many types of cancer.

Background:

When a lump is discovered in a breast, and a tissue biopsy sample is sent to pathology, the pathology report guides the course of the treatment. It tells the cancer tumor’s size, if it has spread or is stable, if it is hormone-receptor positive or negative, and most importantly its ErbB2 receptor count.

About 30 percent of newly diagnosed breast cancer samples will come back from pathology as “ErbB2 / over expression.” Over expression means that the DNA which you were born with, and which is the “build blueprint” for breast tissue, has a genetic defect in its code, and, say, instead of building 100 ErbB2 receptors, it builds 10,000 ErbB2 receptors. This means that when the signal is sent by Akt 1 to grow and build more proteins, the breast tissue is overstimulated, because there are too many ErbB2 receptors built into the cell’s membrane.

Too many signals to grow are sent into the internal machinery inside the cell, the ErbB2 receptors “over-receive and over-send the signal” and may cause normal cells to form cancer or to stimulate any single cancer cells that exist also to grow and multiply out of control and form a tumor over time.

The present drug treatment for ErbB2 driven breast cancer is a drug called Herceptin. This is the trade name under which it is sold; trastuzumab is the generic pharmaceutical name.

Herceptin was originally developed in mice, as a mouse antibody. Because humans have immune reactions to mouse proteins, it was later developed into a humanized antibody. Because the antibodies were produced from one cell that was grown into a clone of identical cells, it is called a monoclonal antibody.

This drug was developed using the same MMTV-neu mouse model as THC was, as described above.

The original studies of trastuzumab showed that it improved survival in late-state (metastatic) breast cancer, but there is controversy over whether trastuzumab is effective in earlier stage breast cancer. Trastuzumab is also controversial because of its cost, as much as $100,000 per year, and while certain private insurance companies in the U.S. and government health systems in Canada, the U.K. and elsewhere have refused to pay for trastuzumab for “certain patients” (code for the poor), some companies have since accepted trastuzumab treatment as covered, preventative treatment.

Think about that: $100,000 for one year of treatment per patient! Let’s see: A thousand patients times $100,000 = $100 million! Ten thousand patients times $100,000 = $1 billion. It’s so expensive that even the U.S. government doesn’t want to pay for it. Somebody, somewhere, is making a lot of money.

Now do you know why cannabis isn’t being researched as a cure? Do you see why some would have a vested interest in stopping it?

Oh, I left out one important fact: Trastuzumab only has a 25 to 30 percent successful rate of cure! And nearly 15 percent of people treated eventually develop new metastases. This drug’s cure rates are no better than the effect of a placebo!

When an experiment is conducted, the new drug being tested has to outperform the “placebo effect” to show it works. The new drug should be in at least the 40 percent range to show its effectiveness. In this case, it failed to do that — yet it is still being prescribed as a main, go-to treatment at $100,000 per year per breast cancer patient.

What happens if you have no health insurance or a job? Is this a crime? You tell me… And cannabis is still illegal?!

Note: About 10 percent of patients are unable to tolerate trastuzumab because of pre-existing heart problems. It causes the heart to pump out less blood volume, leading to congestive heart failure.

A colony of MMTV-neu mice was allowed to mature, and after 36 weeks, 50 percent of the females developed breast cancer.

A sample of 87 grade 3 invasive breast ductal carcinomas in which the cancer had spread to the lungs was chosen to be treated with THC. In the experimental groups, THC-treated mice had fewer and smaller (by weight and size) tumor counts after 90 days of treatment, as documented by microscopic tissue analysis.

“Our results show that down regulation of Akt is involved in cannabinoid anti-tumoral acteion.” When THC down regulated the ArK 1 gene, this “shut down signal” to the ArK 1 gene by THC appears to trigger apoptosis in the ErbB2-driven cancer; “programmed cell death” is executed and the cancer kills itself.

Remember, this is only a phase one study. This effect still needs to be proven in humans. However:

• Akt over-activation has been detected in a significant percentage of primary human breast cancers. THC plays a role in its regulation.

• The cancer growth in humans and the mice is near identical in both cases.

• Treatment with cannabinoids significantly decreased tumor growth, size, and numbers due to the “remarkable growth-inhibitory effects of cannabinoids.”

• THC reduced tumors from growing new blood vessels to feed themselves (anti-angiogenic).

• THC decreased the number of tumors spreading to nearby tissue and the lungs. This was also observed in advance cancer that had spread to the lungs already.

• “Remarkably, this is, to the best of our knowledge, the first report suggesting that cannabinoids hamper not only tumor growth but also tumor generation.”

• “Our data suggest that the endocannabinoid system has a physiological protective role against tumorigenesis, in line with the general idea that this system contributes to maintain homeostasis in health and disease.”