Study on Trans Men Provides Answers for Breast Cancer Treatments

Androgen therapy — also referred to as testosterone replacement therapy — may provide insights into breast cancer treatments.

The new study, led by Cedars-Sinai investigators, featured breast tissue samples from transgender men undergoing gender-affirming androgen therapy followed by subcutaneous mastectomies.

Researchers documented molecular changes in the breast tissue of transgender men involved in androgen therapy, meaning the hormone may be able to resist breast cancer derived from estrogen. The discoveries were published in Cell Genomics on March 8.

Transgender men are registered as female at birth but identify as the male gender. In many cases, transgender men may undergo androgen therapy. Androgens are sex hormones that help individuals enter puberty.

Androgen therapy most commonly uses testosterone, which helps transgender men feel more comfortable in their bodies by exhibiting male characteristics.

During the study, researchers compared breast samples from transgender men undergoing androgen therapy and cisgender females who had previously undergone cosmetic breast surgery.

The study included three different analytic techniques, single-nucleus RNA sequencing (snRNA-seq), assay for transposase-accessible chromatin (ATAC) sequencing, and lastly, co-detection by indexing (CODEX) multiplex immunohistochemistry (IHC).

The first technique, snRNA-seq, helped researchers visualize types of cells within breast tissue affected by androgen and any altered genes. ATAC revealed the chromatin of individual cells. Chromatin is the DNA and proteins that create the genetic martial in the nucleus of cells. The final technique uncovered the results of androgen therapy’s effect on the organization of breast tissue cells.

Transgender men who underwent androgen therapy showed fewer signs of having breast cells influenced by estrogen and produced fewer proteins contributing to milk production by the breasts. Cis-female cells, however, failed to compare.

Androgen therapy successfully helped change the genetic information of the breast cells into that similar to a male. The therapy also caused a shift in the immune cells notably found in breast tissue. Researchers believe this could suggest the immune system is fighting cancer cells.

The study's first author and former graduate student at Cedars-Sinai, Florian Raths, emphasized the importance of the study’s discoveries in a news release.

"The most important aspect of this work is that we have created an atlas of every type of breast cell undergoing androgen therapy," Raths says. "This database can be used by other investigators to study cellular changes following androgen exposure."

Researchers mention limitations like low patient numbers and a lack of sample data. Despite this, they believe the study is a good representation of the effects of hormonal changes on breast cancer cells.

For future steps, researchers hope to survey how low doses of androgen affect high-risk individuals for breast cancer at the molecular level.

Dan Theodorescu, M.D., Ph.D., is the director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. He believes this study will lead to new findings about the interactions of androgen and estrogen that may lead to cancer treatments.

Theodorescu notes Cedars-Sinai is championing the LGBTQ+ community, an often forgotten group.

"Our cancer center is focused on patients and populations such as LGBTQ+ who have historically not been a focus of specific cancer studies," Theodorescu says. "We are trying to change that and to add to the national diversity in cancer research."

Breast cancer in the United States

Breast cancer therapies are in demand. According to the CDC, breast cancer is women's second most common cancer.

The CDC says around 264,000 women are diagnosed with breast cancer each year. Nearly 42,000 women in the U.S. die from breast cancer each year. For men, the amount of breast cancer cases and deaths are far less. Only 2,400 men are diagnosed, and 500 men die from breast cancer yearly.

Keeping a healthy weight and remaining physically active can reduce the chances of breast cancer. The U.S. Surgeon General recommends 30 minutes of activity per day for adults. Also, reducing excessive alcohol consumption and smoking can help lower the risk of developing breast cancer.

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