Exogenous Thyroid Hormone is Associated with Shortened Survival and Upregulation of High Risk Gene Expression Profiles in Steroid Receptor Positive Breast Cancers.

PURPOSE: Thyroid disease is a frequent comorbidity in women with breast cancer (BC), and many require thyroid hormone(TH) replacement therapy(THRT). We postulated that THRT has a deleterious clinical effect mechanistically through hormonal interactions, nuclear receptor cross-talk and upregulation of high-risk BC genes.

EXPERIMENTAL DESIGN: Observational studies of lymph node-negative (LN-) BC patients (n= 820 and n=160) were performed to test interactions between THRT and clinical, histologic, outcome and treatment variables. Differences between the two cohorts include but are not limited to patient numbers, decades of treatment, duration of follow-up/treatment, tumor sizes, incidence, type and dose/regimen of anti-hormonal and/or chemotherapeutic agents. In vivo and vitro models, in silico databases and molecular methods were used to study interactions and define mechanisms underlying THRT effects.

RESULTS: THRT significantly and independently reduced disease-free and BC specific overall survival of only the steroid receptor (SR) positive (as compared to SR negative) node-negative patients in both long-term observational studies. SR+ LN- BC patients who received THRT and tamoxifen experienced the shortest survival of all treatment groups. A less potent interaction between THRT and aromatase inhibitors was noted in the second patient cohort. Using in vivo and in vitro models, TH administration enhanced estrogen and TH associated gene expression and proliferation, nuclear co-localization of ER and THR, as well as activation of genes used clinically to predict tumor aggression in SR+ BC including the IGF-IR, WNT, and TGFβ pathways.

CONCLUSIONS: We show clinically significant adverse interactions between THRT, estrogenic and oncogenic signaling in SR+ LN- BC patients.