Project Summary:
Over 2.5 million American adults identify as transgender and/or gender diverse (TGD), a population that is increasing with time. TGD describes an individual whose gender identity is different from the sex they were assigned at birth. Cisgender describes someone whose gender identity is the same as the sex they were assigned at birth. TGD persons assigned female at birth (TGD-AFB) may use gender-affirming testosterone (GAT) and undergo gender-affirming operations such as gender-affirming chest masculinization surgery (also known as top surgery) to remove most of their breast tissue. While gender-affirming therapies provide significant psychosocial benefits, there are no studies that assess the cellular mechanisms by which GAT changes breast structure and how these changes may influence future breast cancer risk. Breast cancer is the most common cancer in cisgender women and approximately 13% will receive a diagnosis during their lifetime in the U.S. Wisconsin cisgender women have a higher breast cancer incidence rate than the national average at 137 diagnoses per 100,000 cisgender women. Well-established breast cancer risk factors include lifetime estrogen exposure, family history of breast cancer, and environmental exposures.
To date, breast tissue exposed to GAT and procured during top surgery has had limited clinicopathological evaluation, and only three major publications describe these changes. In 2017, East, et al. pathologically evaluated 68 top surgery specimens in tissue exposed to GAT and identified that 40% of cases had fibrocystic changes, 32% with gynaecomastoid changes (tissues features more similar to cisgender men, typically considered rare as seen in only 0.6% of cisgender women), and 16% had fibrosis. Side-by-side histological comparison of control (GAT naive) and GAT breast tissue illustrates the gross and broad structural changes that occur. To facilitate cellular composition changes, hormones play a critical role in regulating gene expression, leading to both immediate and long-term changes in cellular function. Hormones elicit transcriptional changes the direct binding of hormone-receptor complexes to DNA21.
Beyond the immediate classical responses, hormones also alter gene expression through epigenetic modifications, including binding co-regulators that modulate DNA methylation, histone remodeling, and editing histone marks, highlighting the intricate dynamics between hormones and the epigenetic landscape. Thus, it is critical to study both the transcriptional and epigenetic changes that occur with GAT.
Epidemiological data from the Netherlands further suggests that GAT in TGD-AFB appears to reduce breast cancer risk compared to cisgender women (standardized incidence ratio 0.3, 95% CI 0.2–0.4). However, on review of surgical pathology specimens for TGD-AFB who have been on GAT and undergo top surgery, cases of breast atypia, ductal carcinoma in situ, and early-stage invasive breast cancer are still being identified postoperatively on breast tissue specimens. Therefore, it is unclear 1) how GAT influences the transcriptional and epigenetic profiles of breast tissue in TGD-AFB and 2) why GAT appears to be a protective mechanism for breast cancer for some persons but is not fully protective for others.
Across the U.S. and in Wisconsin, a growing number of adults identify as TGD, with approximately 5% of younger adults (ages 18–29) identifying as TGD5. Gender-affirming hormone therapy is generally considered medically safe and provides objective psychosocial benefits. Wisconsin survey data recently showed that nearly 70,000 Wisconsin residents identify as TGD, and observational data indicates that approximately 75% TGD-AFB receive GAT. Thus, understanding the transcriptional and epigenetics changes of GAT on breast tissue will impact an estimated 25,000 Wisconsin residents. Given the increasing use of GAT amongst TGD-AFB and that breast cancer is one of the most common cancers in Wisconsin, it is imperative to understand how GAT influences the epigenetic landscape of breast tissue to understand the underlying mechanisms behind breast cancer development in this population.
This project seeks to identify transcriptional and epigenetic differences between breast tissues of TGD-AFB on GAT versus cisgender women. This will provide foundational data needed to support larger scale investigations on epigenetic changes and longitudinal studies that examine the association of breast cancer risk and incidence in TGD-AFB on GAT. The researchers aim to provide informed gender-affirming care for all Wisconsin TGDAFB residents and predict this study will reveal cellular mechanisms of change, recommend mitigation strategies for the TGD community, and establish partnerships for future translational and epidemiological studies.