2024-01-18 01:06:19
On the trail of the culprits: Researchers have identified the cells from which tumors develop in women with genetic breast cancer. According to this, the cancer begins in a certain type of mammary gland precursor cells. The good news: Experiments on mice show that an already approved cancer drug inhibits this tumor formation. Due to its side effects, the drug is not suitable for preventative therapy. However, the findings provide an approach for new means.
Tumor diseases such as breast cancer, colon cancer and lung cancer are increasingly affecting younger people. In addition to lifestyle, several hereditary mutations are known for breast cancer, which mean that affected women have a 70 percent chance of developing breast cancer during their lifetime – often at a young age.
This fluorescence image shows the breast tissue of a woman with the breast cancer risk mutation BRCA2. © Dr Bianca Capaldo/ WEHI
What happens with the BRCA2 mutation?
One of these genetic risk factors is a mutation in the BRCA2 gene. This gene is normally involved in preventing DNA damage and thus preventing tumor development. However, the mutation means that it does not perform this task adequately. In order to counteract the increased risk of breast cancer, those affected are advised to undergo regular early detection examinations or to have their breasts removed as a precaution.
Until now, little was known regarding how exactly the BRCA2 mutation affects breast tissue and which processes take place before a tumor develops. A team led by Rachel Joyce from the University of Melbourne in Australia has now gotten to the bottom of this question. To do this, the team examined samples from the breast tissue of healthy women with a faulty BRCA2 gene and compared them with tissue samples from women of the same age without the mutation.
Changed cells in the glandular tissue
The researchers noticed a group of certain mammary gland cells that were dividing more frequently in women with the BRCA2 mutation. “Because we found these abnormal cells in most tissue samples from women with the BRCA2 mutation, but not in samples from women without the mutation, we believe that these may be the cells of origin from which breast cancer develops in carriers of the mutation can,” says Joyce.
The cells discovered are so-called luminal progenitor cells. Their production of certain proteins, which are important for growth, among other things, is changed. On the one hand, this promotes the development of cancer, but on the other hand, it also provides a possible target. “The changes might make the cells more susceptible to certain therapies that are intended to prevent or delay the development of breast cancer,” says Joyce’s colleague Rosa Pascual.
Drug delays tumor development in mice
To test this hypothesis, the researchers bred mice with a genetic change that corresponds to the BRCA2 mutation in humans. In fact, if left untreated, these animals developed tumors at a young age. The team administered the cancer drug everolimus to some of the model mice as a preventive measure. This is directed once morest a protein complex called mTORC1, which, among other things, regulates the growth, survival and metabolism of cells and is overactive in the breast tissue of BRCA2 carriers.
The result: “The experiments showed a significant delay in tumor onset in the everolimus group compared to the control group,” reports the research team. While mice without the drug developed tumors following an average of 149 days, treated mice remained tumor-free for more than two months longer.
Approach to preventive therapies
From the researchers’ perspective, drug inhibition of mTORC1 is a promising prevention strategy. For women with a BRCA2 mutation, it might potentially be an alternative to mastectomy in the long term. Even though everolimus has already been approved for patients with recurrent breast cancer, there is still a long way to go before it can be used as a preventive treatment.
“The side effects of everolimus limit its suitability for preventive treatment,” says Joyce’s colleague Geoffrey Lindemann. “Our team would like to further explore which specific parts of protein processing are disrupted and use this information to develop more selective and tolerable preventative treatments.” (Nature Cell Biology, 2024, doi: 10.1038/s41556-023-01315-5)
Quelle: Walter and Eliza Hall Institute
18 January 2024 – Elena Bernard
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