Abstract P5-06-01: The role of thyroid hormones in breast tumorigenesis: A translational study utilizing mouse models, cell culture and patient data

Abstract

Abstract Breast cancer and thyroid hormone signaling have been linked since the 1960s. Breast cancer patients have a higher incidence of thyroid cancer, and thyroid cancer patients have a higher incidence of breast cancer than would be predicted by chance alone, supporting a link between thyroid hormone signaling and breast malignancy. Despite many correlative studies, the role and mechanism of thyroid hormone signaling in mammary tumorigenesis has not been elucidated. Past studies have not comprehensively evaluated thyroid hormones (T3, T4) and thyroid stimulating hormone (TSH) levels with breast cancer status in the same individual. The results are further confounded by issues of temporality; studies have either assessed thyroid hormone levels before or after diagnosis, prohibiting conclusions regarding whether thyroid disruption is a cause or effect of breast cancer. In vitro models demonstrate that mammary cells have thyroid hormone receptors and respond to thyroid hormones; however these studies have not been extended to in vivo models. In the current study, we took a translational approach by combining data from cell culture, mouse models and breast cancer patients from the City of Hope Cancer Registry (CHCR). We used the murine MMTV-PyMT model of breast cancer and treated mice with the anti-thyroid drug PTU; lowering T4 levels and increasing TSH. These mice developed significantly larger mammary tumors than untreated animals or those treated with T4 (p= 0.0012 and p=0.0183, respectively). Next, we showed that MCF10a cells in vitro are sensitive to both T4 and TSH added to the culture medium. We hypothesize that even subtle perturbations in normal thyroid hormone levels can stimulate mammary cell growth, increasing risk of transformation. We extended these findings to a small pilot study of 879 invasive and 136 in situ female breast cancer patients with comprehensive thyroid hormone lab analyses in the CHCR (total=984). Pre-treatment results were available for 44 women. TSH was significantly elevated for invasive versus in situ patients (Pt-test =0.016), regardless of the timing of the test. Pre-treatment TSH levels were significantly increased as the severity of disease increased (Pt-test =0.026). Women diagnosed stage 1 disease with no recurrence had a mean TSH level of 1.68 ± 1.87 (Standard Deviation: SD), whereas women diagnosed with stage 1 disease who returned with metastasis had a mean of 2.64 ± 1.72 SD. In the same women, free T4 and total T4 levels were lower and T3 levels were higher (Pt-test< 0.05) in women with invasive versus in situ disease. These studies support the hypothesis that even minimally dysregulated thyroid hormone levels may increase the risk of breast cancer development and progression to aggressive disease. Many women over the age of 50 suffer from sub-clinical hypothyroidism, and our results suggest that sub-clinical hypothyroidism increases breast cancer risk and disease progression. Interestingly, our data indicate that as disease progresses, dependence on TSH lessens, and the most striking differences may be seen in early and low grade disease. Collectively, our data highlight a need to further investigate the role of sub-clinical hypothyroidism in breast cancer. Citation Format: Franco A, Jolly LA, Russell S, Goldstein L, DeHart J. The role of thyroid hormones in breast tumorigenesis: A translational study utilizing mouse models, cell culture and patient data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-06-01.