Taylor & Francis Group
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Thyroid hormone enhances estrogen-mediated proliferation and cell cycle regulatory pathways in steroid receptor-positive breast Cancer

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posted on 2023-09-19, 06:20 authored by Reema S Wahdan-Alaswad, Susan M Edgerton, Hyun Min Kim, Aik Choon Tan, Bryan R Haugen, Bolin Liu, Ann D Thor

Estrogen receptor (ER) α expression and associated signaling is a major driver of over two-thirds of all breast cancers (BC). ER targeting strategies are typically used as a first-line therapy in patients with steroid receptor positive (SR+) disease. Secondary resistance to anti-estrogenic agents may occur with clonal expansion and disease progression. Mechanisms underlying hormone resistance are an expanding field of significant translational importance. Cross-talk with other nuclear hormones, receptors, and signaling pathways, including thyroid hormones (TH) and their receptors (THRs), have been shown to promote endocrine therapy resistance in some studies. We have shown that TH replacement therapy (THRT) was independently and significantly associated with higher rates of relapse and mortality in SR positive (+), node-negative (LN-) BC patients, whereas it showed no association with outcomes in SR negative (-) patients. LN-, SR+ patients receiving THRT and tamoxifen had the worst outcomes, suggesting a pro-carcinogenic interaction that significantly and independently shortened survival and increased mortality. Using in vivo and in vitro models, we previously showed hormonal cross-talk, altered gene signaling, target gene activation, and resistance to tamoxifen in the presence of TH. In this report, we show TH ± E2 ± tamoxifen inhibits cell cycle control signaling, reduces apoptosis, and enhances cell proliferation, tumor growth, tamoxifen resistance, and clonal expansion. Mechanistically these changes involve numerous genes and pathways, including critical cell cycle regulatory proteins and genes identified using various molecular methods. These studies facilitate a greater mechanistic understanding of the biological and molecular impact of TH on SR+ BC.


The work was supported by the American Cancer Society [ACS-IRG16-184-56]; Cancer League of Colorado [AWD#222569-RW]; Mary Kay Ash Foundation [051-04]; Susan G. Komen [K100575].