Androgen therapy is a treatment that involves administering male hormones, such as testosterone, to individuals with low levels of androgens. Historically, androgen therapy has been used to treat conditions such as hypogonadism and osteoporosis in men, and some researchers have investigated the potential use of androgen therapy for certain breast cancer patients.
Cedars-Sinai researchers discovered new insights into the effects of hormonal treatment for transgender men, which could have implications for the treatment of breast cancer.
Transgender men who were assigned female at birth but now identify as male may use androgen hormones to induce physical changes that help them align their physical appearance with their identified gender. Androgens, such as testosterone, are primarily involved in the development of male traits, though females produce androgens as well.
Molecular changes observed in the breast tissue of transgender men undergoing androgen therapy may signal the potential for also using the hormone to prevent or treat a type of breast cancer that is fueled by estrogen. The findings are published in the peer-reviewed journal Cell Genomics.
The most important aspect of this work is that we have created an atlas of every type of breast cell undergoing androgen therapy. This database can be used by other investigators to study cellular changes following androgen exposure.
Florian Raths
“These findings build on previous work showing that androgen receptor activation suppresses tumor growth in estrogen receptor-positive breast cancer,” said Simon Knott, Ph.D., senior author of the study and assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai. “Androgens appear to counteract estrogen’s effects and may be used to prevent estrogen-driven breast cancers.”
The researchers examined breast tissue samples from transgender men who had gender-affirming androgen therapy and subcutaneous mastectomy. The samples were compared to breast tissues from cisgender women who had cosmetic breast surgery.
Three techniques were used to analyze the samples. Single-nucleus transcriptomics is a technique that involves genetically sequencing nuclear RNA from single cells. This allowed the researchers to learn about the different types of cells in breast tissue that were affected by androgen and the genes that were altered.
Another technique they used allowed them to examine the chromatin of individual cells, allowing the researchers to better understand the cellular processes underlying the observed RNA changes. The third technique used by the researchers was spatial profiling of the tissues, which revealed how androgen therapy changed the organization of cells within the breast tissue.
The researchers discovered that in people who received androgen therapy, breast cells that normally react to estrogen showed fewer signs of being influenced by the hormone than in people who did not receive the therapy.
People who received androgen therapy also produced fewer proteins that aid in the ability of the breasts to produce milk. Instead, the therapy induced breast cells to translate their genetic information in ways that are typical of male breast tissue, where cancer incidence is low. Furthermore, researchers discovered a shift in the number and composition of immune cells commonly found in breast tissue. This change could indicate that the immune system is working against the production of cancer cells.
“The most important aspect of this work is that we have created an atlas of every type of breast cell undergoing androgen therapy,” said Florian Raths, a former graduate student at Cedars-Sinai and first author of the study. “This database can be used by other investigators to study cellular changes following androgen exposure.”
The next step in this line of research, according to Knott, would be to investigate how low doses of androgen administered to people at high risk of estrogen receptor-positive breast cancer affect their breast tissue at the molecular level.
“This research lays the groundwork for future discoveries into how androgen and estrogen interact with one another, which may lead to new cancer therapies,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer Center and the PHASE ONE Foundation Distinguished Chair. “Our cancer center focuses on patients and populations, such as LGBTQ+ people, who have historically been overlooked in cancer research. We are attempting to change this and increase national diversity in cancer research.”
