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Review
. 2022 Oct 19;14(20):5117.
doi: 10.3390/cancers14205117.

Links between Breast and Thyroid Cancer: Hormones, Genetic Susceptibility and Medical Interventions

Man Lu  1 , Hanqing Liu  1 , Bilian Zheng  1 , Shengrong Sun  1 , Chuang Chen  1
Affiliations
Review

Links between Breast and Thyroid Cancer: Hormones, Genetic Susceptibility and Medical Interventions

Man Lu et al. Cancers (Basel). .

Abstract

Breast and thyroid glands are two common sites of female malignancies. Since the late 19th century, physicians have found that the cancers in either thyroid or mammary gland might increase the risk of second primary cancers in the other site. From then on, many observational clinical studies have confirmed the hypothesis and more than one theory has been developed to explain the phenomenon. Since the two glands both have secretory functions and are regulated by the hypothalamic-pituitary axis, they may share some common oncogenic molecular pathways. However, other risks factors, including medical interventions and hormones, are also observed to play a role. This article aims to provide a comprehensive review of the associations between the two cancers. The putative mechanisms, such as hormone alteration, autoimmune attack, genetic predisposition and other life-related factors are reviewed and discussed. Medical interventions, such as chemotherapy and radiotherapy, can also increase the risk of second primary cancers. This review will provide novel insights into the research designs, clinical managements and treatments of thyroid and breast cancer patients.

Keywords: breast cancer; etiology; risk factors; second primary cancer; thyroid cancer; treatment.

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Conflict of interest statement

The authors declare that there are no conflict of interest. Figures were created by Figdraw (www.figdraw.com).

Figures

Figure 1
Figure 1
Summary of the potential links of breast and thyroid cancer. Abbreviation: TC: Thyroid Cancer; T3: Triiodothyronine; T4: Thyroxine; BC: Breast Cancer; I 131Therapy: Radioactive iodine therapy.
Figure 2
Figure 2
Thyroid hormone and estrogen-mediated signaling pathway.Estrogen and TH enhance nuclear localization of both THRɑ and ERɑ in breast cancer cells. Thyroid hormones facilitate the genomic effect of estrogen through ERa which bind estrogen response elements (ERE) [48]. Thyroid hormone and E2 regulate p53 and pRb(retinoblastoma protein) together (Left) [49]. TH can induce aberrant activation of MAP kinase and the PI3 kinase signaling pathways by binding ɑvß3 integrin as well. Metastasis and proliferation of BC is improved by increased C-myc, which is activated by the MAP kinase pathway [18]. TH could induce the high expression of hypoxia inducing factor 1 (HIF-1) and transform growth factor alpha (TGFα) in BC cell lines by activating the PI3K pathway (Right) [47].
Figure 3
Figure 3
Estrogen non-genomic signaling pathway and estrogen-induced ROS generation in thyrocyte. The non-genomic signaling of E2 occurs via the membrane-bound receptor mER, which stimulates activation of the MAP kinase and the PI3 kinase signaling pathways (left). Due to the chromosomal rearrangement of the tyrosine kinase receptor TRKA, PET/PTC genes, BRAF gene, and RAS gene mutation, aberrant activation of the tyrosine kinase pathway occurs. Additionally, the PI3K AKT pathway may also be abnormally activated by mutational inactivation of PTEN. E2 stimulates these pathways [61]. In addition, E2 stimulates NOX4 to product ROS, as well as generates ROS through its own metabolization [65]. NOX4 located in the plasma membrane, endoplasmic reticulum, and nuclear membrane. ROS is able to reach nuclear, then promote some alterations which help thyroid carcinogenesis. DUOX: dual oxidase; E2: estrogen; NOX4: NAPDH oxidase 4; ROS: reactive oxygen species; TPO: thyroperoxidase.
Figure 4
Figure 4
Summary of genetic susceptibility of BC and TC. In part 1, PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) is due to germline mutations of tumor suppressor gene: phosphatase and tensin homolog (PTEN). The gene mutation of PTEN upregulates the PI3K-AKT pathway. SDHx (the succinate dehydrogenase complex) mutations can dysregulate TP53 by upregulating p53 proteasomal. KLLN gene encodes the KLLN protein, which is a transcription factor. KLLN mutation influences TP53 dysregulation. In part 2, PARP4 gene encodes poly-ADP-ribose polymerases (PARPs) and is an important component of DNA repair. MANCR (mitotically-associated long noncoding RNA) is an important regulator of the genomic stability of aggressive breast cancer. The vascular endothelial growth factor (VEGF) was overexpressed in TC and BC. In part 3, increased oncogenic single nucleotide polymorphism (SNP) burden in co-occurrence of BC and TC.
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Grants and funding

This research was supported by the grants from Beijing Xisike Clinical Oncology Research Foundation (Y-SY201901-0189), the Fundamental Research Funds for the Central Universities (2042019kf0229), the Science and Technology Major Project of Hubei Province (Next-Generation AI Technologies) (2019AEA170), and the National Natural Science Foundation of China (grant no. 82103671).

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