Study of trans men suggests that androgen hormone therapy can lower breast cancer risk

When transgender men transition, their risk for breast cancer tends to plummet and look more like the breast cancer risk for cisgender men, excluding those with high-risk mutations like BRCA1 or BRCA2. Many researchers thought the main reason for this was probably breast removal during chest reconstruction surgery, but recent research suggests that the androgens during hormone replacement therapy may also play a crucial role in reshaping transgender men’s breast cancer risk.

That’s hinted to researchers that androgens, the male sex hormones, might offer new paths to develop powerful therapies to treat or prevent breast cancer.

In a study published on Wednesday in Cell Genomics, scientists at Cedars-Sinai Medical Center in Los Angeles analyzed individual cells from breast tissue in trans men and cis women. “The goal was to analyze the impacts of androgen on the normal, healthy breast,” said Simon Knott, a computational biologist at Cedars-Sinai and a senior author on the study.

To do this study, Knott and his colleagues studied breast tissue from trans men that was donated after gender-affirming surgery and breast tissue from cis women that was donated after cosmetic breast surgery. Then, they analyzed the tissue on the single cell level to understand the genetic changes that happen in the breast after androgen therapy.

“One of the key things that popped out when we started to look was many of the changes induced by androgen seemed like changes that were the opposite of what you’d expect to see during malignant transformation,” Knott said.

That suggested that the hormone therapy might actually protect against breast cancer, Knott said. Researchers Wayne Tilley and Theresa Hickey from the University of Adelaide, both of whom worked on this study, had previously published in Nature Medicine work “showing definitively that androgen is a break on estrogen receptor signaling and is suppressive against estrogen receptor positive breast cancer growth,” Knott said. “So, the hint that androgen might be protective against breast cancer was not completely unexpected.”

STAT spoke with Knott about the new study, research on trans health and cancer, and how androgens could help treat breast cancer. This interview has been edited for length and clarity.

How did the study start and how did you do it?

The original impetus came from my collaborator Xiaojiang Cui, who is a breast cancer researcher, and Edward Ray, a surgeon focusing on transgender reconstructive surgeries. They had recognized that while estrogen and progesterone have been studied for their impact on the breast and breast cancer, very little is known about how androgen impacts the breast. So, it wasn’t necessarily initiated as a cancer-specific study. Cui and Ed Ray had this bank of tissues from transgender men and cisgender women, and we decided the time was ripe to apply some of these single-cell technologies to unravel how androgen impacts the breast.

We applied three different molecular assays. We analyzed with something called single nuclei RNA sequencing, which sequences the RNA from each individual nucleus from cells. That allows you to identify all the cell types and the gene expression changes from androgen therapy. We also used single nuclei ATAC sequencing, which also involves extracting individual nuclei but allows you to understand the chromatin architecture. Finally, we used a high multiplex staining assay that allowed us to identify all cell types and how they’re spatially organized from one another and how androgen impacted that organization.

What were some of the key findings?

One of the biggest, most striking changes was that androgen appears to induce almost male characteristics in the breast. For example, one of the transcription factors, which regulate overall gene expression, that was most significantly upregulated is CUX2. This is expressed at highest levels in the male prostate, never really seen in the breast.

We looked at this in many ways. There’s a tissue database called GTEx where they’ve profiled male and female tissues from a variety of organs, and we also found that many of the changes we saw from androgens in the epithelial compartment, fibroblast compartment, vascular compartments were also represented in this male versus female gene expression data. Basically, we saw our changes corresponded to the changes when you compare a cisgender male to a cisgender female. One of the other, very obvious changes was the breast cells that appear to show the highest level of estrogen receptor signaling were reduced dramatically in proportion to the androgen-treated breast.

What impact does that have on the risk — or potential treatment of — breast cancer?

That tells us androgen therapy and activation of androgen receptors counteracts estrogen receptor signaling. ER signaling and an overabundance of it is probably one of the greatest causes of breast cancer. ER+ breast cancers count for the majority of breast cancers, and they’re driven by estrogen receptor signaling. So, that indicates to us that activating the androgen receptor would likely be protective against future breast cancer, particularly for ER+ cancers.

Now people might say, high doses of androgen might be protective but what comes with that are male characteristics that breast cancer patients or women at high risk of breast cancer might be unwilling to deal with. So, we’ve started collaborating with the Tilley and Hickey labs from Adelaide to analyze if we can get good results from a low dose of androgen that would bring about anti-estrogen changes that we think are protective without the male external physical characteristics.

Or like using a local application of androgens around the tumor area?

That’s a potential possibility, like an intraductal injection of androgen or a topical cream. In an anecdotal way, the Tilley and Hickey labs have shown that a low dose of androgen does not induce male characteristics, but breast density can be reduced. High breast density is a major risk factor of breast cancer.

Does this work tell us anything about whether trans men should get screening for breast cancer or gynecological cancers — and how often?

Screening and incidence and therapeutics for trans individuals is something really being studied and developed at Cedars-Sinai in our trans health center as well as our cancer center. In terms of our study, we can potentially explain the risk of breast cancer in trans men through our findings. The reversal of estrogen receptor signaling and other signaling in the androgen treated breast might indicate a more protective tissue environment.

One thing we saw was a significant increase in activated helper T cells that appeared to be honed in on the breast epithelium. That indicates the adaptive immune system is surveilling that tissue more actively after androgen therapy. We also saw reduced macrophages, which can cause inflammation. Based on this study, a reasonable assessment is to say that trans men should be treated as cis men in terms of breast screening.

How could future studies done with trans people help cancer research and trans health?

The incidence of breast cancer in trans men are extremely low, so studying breakthrough cases — where trans men have actually gotten a breast cancer — would be interesting to understand when this fails and how. I also think it would be worth looking at the breast tissue of trans women who typically receive high doses of feminizing hormones like estrogen to induce the growth of breast. Looking at that tissue where there is an increased incidence of breast cancer and understanding the molecular mechanisms underlying that — and the reciprocal action of androgen might better elucidate how these two hormones interact with one another.