Masculinizing hormone therapy effect on breast tissue: Changes in estrogen and androgen receptors in transgender female-to-male mastectomies.

PURPOSE: Almost two percent of individuals in the United States identify as gender non-conforming. In the female-to-male (FTM) transgender population, masculinizing hormone therapy with testosterone is commonly prescribed in gender transition. To date, the effects of exogenous androgens on breast tissue and its roles in altering breast cancer risk are poorly understood. This study examines the histopathologic findings in gender affirming mastectomy (GAM) in transgender FTM patients and the effects of exogenous androgens on estrogen receptors (ER) and androgen receptors (AR). METHODS: A retrospective review of pathology specimens obtained between 2017 and 2020 was performed comparing androgen exposed breast tissue with breast tissue without androgen exposure. Breast specimens were obtained from patients who underwent FTM GAM with recorded exogenous androgen exposure. Control breast specimens were obtained from reduction mammoplasty (RM) procedures in cisgender women which were aged matched to the GAM cohort, as well as postmenopausal women with benign/prophylactic mastectomy procedures; all controls were without androgen exposure. The histopathologic findings were assessed. Immunohistochemistry for AR and ER was performed and the score interpreted by digital image analysis. RESULTS: Androgen-exposed breast tissue revealed dense fibrotic stroma, lobular atrophy, thickened lobular basement membranes, and gynecomastoid changes. Longer duration of androgen exposure resulted in a more pronounced effect. The incidence of atypia or cancer was lower in GAM than RM cohort. ER and AR expression was highest in transgender male breast tissue with intermediate duration of exogenous androgen exposure. CONCLUSION: Increased androgen exposure is associated with lobular atrophy and gynecomastoid changes in breast parenchyma. Overall, ER and AR are expressed strongly in lobular epithelium in patients with prolonged androgen exposure. Exogenous testosterone does not appear to increase risk for breast cancer. Additional studies are needed to investigate the mechanism responsible for these changes at a cellular level and its role in cancer development

miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and β-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC