Razi Journal of Medical Sciences

Background & Aims: Thyroid and breast glands are two common sites of female malignancies. Since the late 19th century, it was recognized that thyroid or breast cancers may increase the risk of second primary cancers elsewhere. Since then, many observational clinical studies have confirmed this hypothesis and more than one theory has been developed to explain this phenomenon.
Methods: The present article is a review study that was conducted in foreign databases including Web-of-Science, Scopus, PubMed, along with the Google Scholar search engine; and the Iranian databases of the Academic Jihad Scientific Information Center, Magiran, and Irandoc were searched using the keywords " سرطان پستان", "سرطان تیروئید", "Breast cancer" and "Thyroid cancer" in a period of five years, between 2017-2023. Inclusion criteria in this study were research and review articles related to the relationship between breast cancer and thyroid cancer in the world, publication of articles in English or Persian, in domestic and foreign scientific journals, and access to the full text of the article, and irrelevant, repeated studies, with languages other than English or Farsi, weak connection with the purpose of the study, lack of appropriate implementation method, lack of necessary quality in terms of reporting the desired findings, books, dissertations, letters to the editor, editor's article, conference article, were discarded. In the search phase, the found articles were reviewed based on the inclusion criteria. Then, the remaining eligible articles were evaluated and analyzed in terms of content. The result of the initial search was 276 studies, of which 225 studies were removed after reviewing the title and purpose, 20 studies after reviewing the abstract, 15 studies after full text review, and 2 studies were added as a result of manual search. Finally, 18 studies were eligible for the current research. After the evaluation of these studies, the data were analyzed by comparing, summarizing and determining validity. Due to the wide range of studies on the relationship between thyroid gland and related diseases and breast cancer, in this review article, only the relationship between breast cancer and thyroid cancer has been discussed. Two hypotheses have been proposed for this relationship. First, human chorionic gonadotropin (hCG) produced by the placenta, because hCG has a similar thyroid-stimulating function as thyroid-stimulating hormone (TSH) and may promote breast cancer through the secretion of thyroid hormones (THs). Second, thyrotropin-releasing hormone (TRH) stimulated by lactation during the postpartum period stimulates not only TSH secretion and thus indirectly THs, but also prolactin (PRL), which can accelerate breast cancer progression. These hypotheses also explain the temporary increase in breast cancer risk during pregnancy, while estrogen inhibition by PRL may have a long-term preventive effect on breast cancer. Pregnancy-related hyperthyroidism may also be the predominant cause of thyroid disease in women in general, as well as tumors in the organs that thyroid hormone targets.
Results: Since these two glands both have a secretory function and are regulated by the hypothalamus-pituitary axis, they may have common oncogenic molecular pathways. However, other risk factors, including medical interventions and hormones, also play a role. The purpose of this article is to comprehensively investigate the relationship between these two cancers. Possible mechanisms, such as hormone changes, autoimmune attack, genetic predisposition, and other life-related factors are explored and discussed. Medical interventions such as chemotherapy and radiotherapy can also increase the risk of second primary cancers. Both the thyroid and the breast require iodide to produce iodoproteins that participate in TH biosynthesis and breast milk as a source of nutrition for infants. The sodium iodide symporter (NIS), a membrane-bound glycoprotein, is located in the basal cell membrane. Its function is to transport and accumulate iodide ion (I-) inside the cell. NIS mediates active I- uptake in the thyroid, which is an important step in thyroid hormone biosynthesis. Besides the thyroid, NIS can mediate I- uptake in other tissues, such as salivary glands, gastric mucosa, and mammary glands. NIS expression has been observed in more than 80% of breast cancer samples and 23% of breast tumor margin samples. Benign breast diseases, such as fibroadenoma, show increased expression of NIS proteins and iodide accumulation. Not all second cancers are attributable to the molecular immunological environment, hormones, or the oncogenic effects of primary cancer treatments. Some sporadic cases may be attributed to genetic susceptibility and lifestyle factors. A large retrospective study among twins in Northern European countries found that heritability accounts for approximately 33% of cancer risk. Thyroid hormones (TH) have important effects on skeletal growth, basal metabolism, nervous system development, and cell proliferation and differentiation. Mammary glands are target tissues for THs and their effects are complex. Hypothyroidism after surgery is a common complication in thyroid cancer patients. Previous studies have shown that TH disorders, such as hyperthyroidism and hypothyroidism, can affect the risk of cancers arising from glandular epithelium.
 Autoimmune thyroid diseases (ATD) include Graves' disease and Hashimoto's thyroiditis. Two Hashimoto's thyroiditis-specific biomarkers, thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), are present in 90% of patients. Thyroid-stimulating hormone antibody (TSHRab), which can bind to TSHR and increase TH synthesis and release, is a specific biomarker for Graves' disease. Generally, the proposed mechanisms between ATD and cancer can be explained in two ways. On the one hand, the disordered immune system is not able to destroy cancer cells. On the other hand, a damaged immune system is prone to attack both normal and abnormal cells. A high rate of BC in ATD women was observed in 1975. The researchers found 18 BC cases in 1,810 cases of Hashimoto's thyroiditis, which was much higher than expected (3.19 cases). The relationship between ATD and BC has since been investigated. Since the 1940s, radioactive iodine (RAI) has been used in the treatment of hyperthyroidism. Radioactive iodine therapy after surgery is also used in patients with neck lymph node metastasis, distant metastasis and extrathyroidal extension. Radioactive iodine can be transferred to thyroid epithelial cells through NIS to exert a tumoricidal effect. NIS is also expressed in the breast, salivary lacrimal glands, ovaries, and gastric mucosa. Furthermore, BC cells have been shown to have functional expression of NIS. Regarding the possible increase in the incidence and mortality of the second primary malignancy, including breast cancer, concerns have been raised about radioactive iodine treatment.
Conclusion: The association between BC and TC has been evaluated. Patients who have either cancer history are at an increased risk of the other second primary cancer compared to the general population. “What is the mechanism?”, this problem has been illustrated and explored partially. The shared common features may be the etiologies and possible causative factors of BC and TC. For example, the hormone effects of TH and E2, autoimmune attack, genetic predisposition and other life-related factors. However, some results remain inconsistent. Well-designed and large cohort studies are needed to prove the causative factors linking BC and TC. Further investigation into gene mutation and disordered gene expression underlying BC and TC development is promising. Complicated, different, and cross-talk signal pathways exploration is needed as well. On one hand, RAI therapy should be taken into consideration by clinicians when balancing the benefits and risks. On the other hand, systematic chemotherapy and partial external beam radiation can both affect the thyroid gland. Systematic chemotherapy and immunity therapy lack convincing evidence to support their relation with TC. Large cohort studies are needed to evaluate the oncogenic effect of external beam radiation on certain regions. Common tumorigenic pathways to BC and TC and shared risk factors can be screened. The studies on co-occurrence of BC and TC can reveal the biological behavior of two cancers and provide novel treatment strategies, which might guide clinical practice in the future.