Study of androgen therapy for transgender men may lead to new breast cancer treatments
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Key takeaways:
- Androgen receptor activation counteracted high levels of ER activity.
- The findings suggest that androgen receptor activation may have a role in the development of future therapies for ER-positive breast cancer.
A therapy commonly used for gender affirmation in transgender men potentially could have a role in the development of therapies for ER-positive breast cancer, according to a study published in Cell Genomics.
Researchers identified molecular changes in the breast tissue of transgender men undergoing androgen therapy that suggest the hormone may have utility in treating or preventing ER-positive breast cancer.
“Estrogen receptors and progesterone receptors have certainly been an area of focus in terms of how hormone receptors regulate breast development and lactation, but although there have been studies in this area, the role that androgens or the androgen receptor plays in the normal human breast is not entirely known,” Simon Knott, PhD, assistant professor of biomedical sciences and medicine at Cedars-Sinai Medical Center and senior author of the study, told Healio. “So, my collaborators, one of whom is a transgender surgeon who works with transgender men all the time, recognized that this is an important question.”
Knott spoke with Healio about his study’s findings and what they may mean for the future development of therapies for breast cancer.
Healio: What prompted you to study androgen therapy in relation to breast cancer?
Knott: Two of my collaborators and co-senior authors on the paper, Xiaojiang Cui, PhD, and Edward Ray, MD, recognized that we didn’t know a whole lot about androgen and androgen receptor activity in the breast and how it impacts breast homeostasis. They started to collect some of the tissue that Dr. Ray was taking out of transgender men and storing it for future experiments. I was working with [Ray and Cui] on another project, and they mentioned that they had these samples. We put our heads together and realized that by combining these samples with some of the technologies I had in the lab, we would be able to give the research community a good view of how androgen, through the androgen receptor, regulates the breast. The tissue was taken from individuals who had taken gender-affirming androgen therapy and then had a scheduled gender-affirming surgery to remove the remaining tissue. So, these patients were on androgen therapy right up to the point of breasts removal.
Healio: How did you assess the samples?
Knott: We used single-nuclei RNA sequencing, which enabled us to look at the individual cells and their gene expression patterns and to understand how cell proportions and cell phenotypes change during androgen therapy. We also used single-nuclei ATAC sequencing, which permitted us to study chromatin features at the single-cell level. With that information, we were able to infer what transcriptional regulatory machinery within each cell was causing the observed phenotypic changes.
Then, as a final analysis, we incorporated highly multiplexed immunohistochemistry in the form of co-detection by indexing. That allowed us to look at the spatial staining patterns of about 35 proteins simultaneously. That, in turn, allowed us to study each breast cell type spatially and to understand how androgen influences cell-cell interactions and the overall tissue architecture of the breast.
Healio: What did you find?
Knott: Looking at the gene expression data, we found significant gene expression changes in cells that had androgen receptor expression and also in cells that did not. This indicated that androgens can speak to cells through the androgen receptor, but also that cells that don’t have this receptor can indirectly accept hormone signals, likely through signals emitted from cells expressing the androgen receptor.
Our chromatin analysis allowed us to infer which changes were directly androgen-receptor associated and which were not. For those that were not, it allowed us to understand the transcription factors involved. In the case of changes that were directly related to androgen receptor activity, these data also allowed us to understand other proteins that were potentially working with the androgen receptor at chromosomal loci to influence gene expression.
The third technology, the spatial profiling, allowed us to understand the morphologic outputs from these phenotypic changes. Are certain cells more likely to be neighboring other cells after androgen therapy? How is the immune infiltration in the breast altered by therapy? That allowed us to see that the immune architecture is, in fact, altered dramatically by the therapy, in that there is an increase in activated, nonregulatory CD4 T cells and a decrease in macrophage infiltrate.
Healio: What are the implications of these findings?
Knott: One key finding was that androgen therapy seems to significantly decrease the proportion of breast epithelial cells showing high levels of ER signaling. This would indicate that androgen receptor activation counteracts ER activity. We know that ER-positive breast cancers are driven by ER signaling. So, putting A and B together, you would then predict that androgen therapy would be detrimental to the formation of ER-positive breast cancers or to ER-positive breast cancer growth.
This seems to be true. As we were performing this study, a publication came out in Nature Medicine from an Australian group that showed fairly definitively that the androgen receptor is a tumor suppressor for ER-positive breast cancer. It further showed that the mechanism of action is essentially through the androgen receptor acting like a natural homeostatic break on ER signaling. So, our data correlated very, very well with their tumor data and indicated that not only could androgen receptor activation be used as a treatment in the malignant setting, but that the therapy may also be effective in the preventive setting.
Healio: What is next for your research on this?
Knott: We’re starting to work with that Australian group and other clinical collaborators to understand what lower doses of androgens do to the normal breast, the breast at high risk for developing breast cancer, and breasts that have “premalignant” lesions like ductal carcinoma in situ.
References:
- Hickey TE, et al. Nat Med. 2021;doi:10.1038/s41591-020-01168-7.
- Raths F, et al. Cell Genom. 2023;doi:10.1016/j.xgen.2023.100272.
For more information:
Simon Knott, PhD, can be reached at Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048; email: simon.knott@cshs.org.
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