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      Implication from thyroid function decreasing during chemotherapy in breast cancer patients: chemosensitization role of triiodothyronine

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          Abstract

          Background

          Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.

          Methods

          Thyroid hormones and NTIS prevalence at initial diagnosis and during chemotherapy were analyzed in 685 breast diseases patients (369 breast cancer, 316 breast benign lesions). The influence of thyroid hormones on chemotherapeutic efficacy was evaluated by chemosensitization test, to compare chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T 3) and chemotherapeutics only.

          Results

          In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased signigicantly during chemotherapy. T 3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T 3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T 3, finding pretreatment with lower dose of T 3, using higher dose of T 3 together with 5-Fu or during chemotherapy with 5-Fu were all available to achieve chemosensitization, but pretreatment with lower dose of T 3 until the end of chemotherapy may be a safer and more efficient therapy.

          Conclusions

          Taken together, thyroid hormones decreasing during chemotherapy was found in lots of breast cancer patients. On the other hand, thyroid hormones can enhance the chemotherapeutic efficacy through gatherring tumor cells in actively proliferating stage, which may provide a new adjuvant therapy for breast cancer in furture, especially for those have hypothyroidism during chemotherapy.

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          Most cited references39

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          Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma.

          Massimo Cristofanilli, Yuko Yamamura, Shu-Wan C Kau … (2005)
          To investigate the role of primary hypothyroidism (HYPT) on breast carcinogenesis, the authors evaluated 1) the association between HYPT and a diagnosis of invasive breast carcinoma and 2) the clinicopathologic characteristics of breast carcinoma in patients with HYPT. For this retrospective chart review study, 1136 women with primary breast carcinoma (PBC) were identified from the authors' departmental data base. These women (cases) were frequency-matched for age (+/- 5 years) and ethnicity with 1088 healthy participants (controls) who attended a breast carcinona screening clinic. Women with HYPT who were receiving thyroid-replacement therapy before they were diagnosed with breast carcinoma or before the screening visit were identified. The mean ages of cases and controls (51.6 years vs. 51.0 years, respectively; P = 0.30) and their menopausal status (65.4% premenopausal vs. 62% postmenopausal; P = 0.10) were comparable. Two hundred forty-two women in the case group (10.9%) with HYPT were identified. The prevalence of this condition was significantly greater the control group compared with the case group (14.9% vs. 7.0%, respectively; P < 0.001). PBC patients were 57% less likely to have HYPT compared with their healthy counterparts (odds ratio, 0.43l 95% confidence interval, 0.33-0.57). Seventy-eight white patients with PBC had HYPT and, compared with women who were euthyroid, they were older at the time of diagnosis (58.8 years vs. 51.1 years; P < 0.001), were more likely to have localized disease (95.0% vs. 85.9% clinical T1 or T2 disease, respectively; P = 0.025), and were more likely to have no pathologic lymph node involvement (62.8% vs. 54.4%; P = 0.15). Primary HYPT was associated with a reduced risk for PBC and a more indolent invasive disease. These data suggest a possible biologic role for thyroid hormone in the etiology of breast carcinoma and indicate areas of research for the prevention and treatment of breast carcinoma.
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            Hyperthyroidism.

            B. D. Cooper (2003)
            Hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating thyroid hormone. The most common cause of this syndrome is Graves' disease, followed by toxic multinodular goitre, and solitary hyperfunctioning nodules. Autoimmune postpartum and subacute thyroiditis, tumours that secrete thyrotropin, and drug-induced thyroid dysfunction, are also important causes. The diagnosis of hyperthyroidism is generally straightforward, with raised serum thyroid hormones and suppressed serum thyrotropin in almost all cases. Appropriate treatment of hyperthyroidism relies on identification of the underlying cause. Antithyroid drugs, radioactive iodine, and surgery are the traditional treatments for the three common forms of hyperthyroidism. Beta-adrenergic blocking agents are used in most patients for symptomatic relief, and might be the only treatment needed for thyroiditis, which is transient. The more unusual causes of hyperthyroidism, including struma ovarii, thyrotropin-secreting tumours, choriocarcinoma, and amiodarone-induced thyrotoxicosis are, more often than not, a challenge to diagnose and treat.
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              Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid.

              Jerome Hershman (2004)
              Human chorionic gonadotropin (hCG) is a glycoprotein hormone that has structural similarity to TSH. At the time of the peak hCG levels in normal pregnancy, serum TSH levels fall and bear a mirror image to the hCG peak. This reduction in TSH suggests that hCG causes an increased secretion of T4 and T3. Women with hyperemisis gravidarum often have high hCG levels that cause transient hyperthyroidsm. In the vast majority of such patients, there will be spontaneous remission of the increased thyroid function when the vomiting stops in several weeks. When there are clinical features of hyperthyroidism, it is be reasonable to treat with antithyroid drugs or a beta-adrenergic blocker, but treatment is rarely required beyond 22 weeks of gestation. Hyperthyroidism or increased thyroid function has been reported in many patients with trophoblastic tumors, either hydatiditform mole or choriocarcinoma. The diagnosis of hydatidiform mole is made by ultrasonography that shows a 'snowstorm' appearance without a fetus. Hydatidiform moles secrete large amounts of hCG proportional to the mass of the tumor. The development of hyperthyroidism requires hCG levels of >200 U/ml that are sustained for several weeks. Removal of the mole cures the hyperthyroidism. There have been many case reports of hyperthyroidism in women with choriocarcinoma and high hCG levels. The principal therapy is chemotherapy, usually given at a specialized center. With effective chemotherapy, long-term survival exceeds 95%. A unique family with recurrent gestational hyperthyroidism associated with hyperemesis gravidarum was found to have a mutation in the extracellular domain of the TSH receptor that made it responsive to normal levels of hCG.
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                Author and article information

                Contributors
                Jianbo Huang
                Liangbin Jin
                Guangyan Ji
                Lei Xing
                Chaobo Xu
                Xiong Xiong
                Hongyuan Li
                Kainan Wu
                Guosheng Ren
                Lingquan Kong
                Journal
                Journal ID (nlm-ta): BMC Cancer
                Journal ID (iso-abbrev): BMC Cancer
                Title: BMC Cancer
                Publisher: BioMed Central
                ISSN (Electronic): 1471-2407
                Publication date Collection: 2013
                Publication date (Electronic): 6 July 2013
                Volume: 13
                Page: 334
                Affiliations
                [1 ]Department of Endocrine & Breast Surgery, the First Affiliated Hospital of Chongqing Medical University, You Yi Rd. 1, Chongqing, People’s Republic of China
                Article
                Publisher ID: 1471-2407-13-334
                DOI: 10.1186/1471-2407-13-334
                PMC ID: 3717040
                PubMed ID: 23829347
                SO-VID: 514b2e78-2e2a-49c6-a3c1-d9020819bb04
                Copyright © Copyright © 2013 Huang et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 4 October 2012
                Date accepted : 30 June 2013
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer,thyroid hormones,non-thyroidal illness syndrome,chemotherapeutic efficacy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: breast cancer, thyroid hormones, non-thyroidal illness syndrome, chemotherapeutic efficacy

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