Hormonal Crosstalk Between Thyroid and Breast Cancer

Abstract

Differentiated thyroid cancer and breast cancer account for a significant portion of endocrine-related malignancies and predominately affect women. As hormonally responsive tissues, the breast and thyroid share endocrine signaling. Breast cells are responsive to thyroid hormone signaling and are affected by altered thyroid hormone levels. Thyroid cells are responsive to sex hormones, particularly estrogen, and undergo protumorigenic processes upon estrogen stimulation. Thyroid and sex hormones also display significant transcriptional crosstalk that influences oncogenesis and treatment sensitivity. Obesity-related adipocyte alterations—adipocyte estrogen production, inflammation, feeding hormone dysregulation, and metabolic syndromes—promote hormonal alterations in breast and thyroid tissues. Environmental toxicants disrupt endocrine systems, including breast and thyroid homeostasis, and influence pathologic processes in both organs through hormone mimetic action. In this brief review, we discuss the hormonal connections between the breast and thyroid and perspectives on hormonal therapies for breast and thyroid cancer. Future research efforts should acknowledge and further explore the hormonal crosstalk of these tissues in an effort to further understand the prevalence of thyroid and breast cancer in women and to identify potential therapeutic options.

Breast cancer (BC) and thyroid cancer (TC) are among the most common malignancies in women, with respectively, 84.8 and 23.1 new cases per 100 000 annually in North America (1, 2). Of cancers in women worldwide, breast and thyroid malignancies are the first and eleventh respective leading diagnoses (1, 3). Both cancers have a significant sex disparity: women have a 100 times greater BC risk and 2.9 times greater TC risk than men (4, 5). Incidence rates for both BC and TC have increased in the last several decades with a 1.9-fold increase in BC (women 25 to 39 years of age) and 2.9-fold increase in TC (3, 6). Combined morbidity and increasing prevalence of these malignancies warrant continued investigation of causes and underlying biological susceptibilities.

A growing body of literature supports a link between BC and TC. The observed co-occurrence of TC and BC is significant; observational and epidemiological studies identify a bidirectional risk increase between BC and thyroid dysfunction or TC (7-10). Survivorship studies suggest a 1.55-fold increased risk for developing secondary TC among BC survivors and a 1.32-fold increased risk for developing BC among TC survivors, relative to the general population (10). Hormone receptor and HER2 receptor positivity are elevated in these metachronous cases, suggesting a hormonal connection between breast and thyroid malignancies (11-13). In rare cases, TC and BC present synchronously, prompting debate as to the role of hormones, genetics, and radiation exposure in BC and TC co-development (14, 15).

Likely, several biological mechanisms influence mutual risk of BC and TC. Radiation and alkylating chemotherapeutics for treatment of primary cancers are well-established risk factors for secondary malignancy (16-18). Particularly, triple-negative BC is not responsive to hormonal therapies, requiring radiation and chemotherapy. Other theories, including shared genetic drivers, account for BC and TC co-occurrence irrespective of prior interventional risk (eg, patients with PTEN hamartoma tumor syndrome, previously referred to as Cowden disease, named after the index, eponymous patient Rachel Cowden by Lloyd and Dennis) (19, 20). However, despite sharing many hormonal components within hypothalamic-pituitary pathways, the thyroid and breast are commonly viewed as separate endocrine tissues. Discussion of breast and thyroid hormone crosstalk within the setting of carcinogenesis is notably lacking, yet some recent reviews have incorporated hormone action within conventional risk factors (21-24). Here, we discuss the thyroid and breast systems as connected endocrine systems in which hormonal crosstalk influences tissue-specific oncologic processes.

Clinical and Physiological Connections

Thyroid Endocrine Signaling

The hypothalamic-pituitary-thyroid (HPT) axis is a negative feedback loop that regulates production of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). Upon thyroid-stimulating hormone (TSH) activation, the thyroid releases thyroid hormones—primarily the prohormone T4—with tissue-specific conversion into T3 by deiodinase enzymes in target cells (Fig. 1). Both benign and malignant thyroid disorders alter the HPT axis and thyroid hormone signaling. Hypothyroidism (ie, congenital and acquired) and hyperthyroidism present with alterations to serum thyroid hormone levels and TSH, while TC is most commonly associated with normal thyroid hormone production and asymptomatic nodules detected on physical exam or thyroid ultrasound (25). Disruption to any portion of the HPT axis, whether from benign or malignant pathologies, alters physiological thyroid equilibria and often requires lifelong, exogenous thyroid hormone supplementation (26).

Figure 1.

Breast and thyroid within the hypothalamic-pituitary hormone system. The hypothalamus is a part of the brain that secretes gonadotropin (GnRH)- and thyrotropin (TRH)- releasing hormones, which stimulate the anterior pituitary gland. In response to these hormones, the pituitary gland activates the thyroid via thyroid-stimulating hormone (TSH) and the gonadal axes via luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Endocrine targets downstream of the anterior pituitary gland, such as the thyroid and ovaries, release thyroid hormones (T3 and T4) or androgens, estrogen, and progesterone to regulate various physiological targets, including the thyroid and breast. Figure created with BioRender.com.

While not often considered a primary HPT target, breast tissue is responsive to thyroid hormone (Fig. 1) (27). Thyroid hormone dysfunction, particularly hyperthyroidism, is associated with increased risk of BC, yet the effects of hypothyroidism are unclear (7, 8, 28-30). Elevated free T4 is associated with risk of several solid cancers, including BC (31, 32). Even in the absence of hormonal or HER2 receptor positivity, T4 influences native immunologic response to BC (33). Additionally, several studies report a general association between all benign thyroid diseases, including non-autoimmune and autoimmune-related thyroid dysfunction, and BC (34-38). Autoantibodies in autoimmune thyroid disorders are independent predictors of BC, especially those directed against thyroid peroxidase and the TSH receptor (TSHR) (34, 39-45). Normal and cancerous breast tissues express structurally similar thyroid peroxidase and TSHR analogs that may be cross-reactive to thyroid-associated autoantibodies (46, 47). Benign breast tissue expresses sodium-iodine symporters (NIS) similar to thyroid tissue, and high dose radioactive iodine (RAI) for treatment of thyroid disease is associated with RAI uptake, with mixed data on whether there is an increased risk of BC (48-52). These clinical observations substantiate an evolutionary and functional connection of the breast to thyroid physiology.

Breast Endocrine Signaling

Breast tissue is a primary target for estrogen and progesterone within the hypothalamic-pituitary-gonadal endocrine axis. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are released from the anterior pituitary in pulsed cycles and regulated by gonadotropin-releasing hormone from the hypothalamus (53). In premenopausal women, estrogen and progesterone are produced primarily from the ovaries and are sensitive to dynamic daily and monthly rhythmic cycles of FSH and LH during the menstrual cycle (Fig. 1). Following menopause, estrogen production declines and shifts to extragonadal tissues, primarily adipocytes, which express aromatase enzymes for conversion of androgens to local estradiol (54-56). Elevated endogenous sex hormones—estrogen, progesterone, androgens—are associated with an increased risk of developing BC both pre- and postmenopause (57-62). Hormone replacement therapy (HRT) was a common treatment in the United States for postmenopausal symptoms with mixed data on a link between HRT and BC risk, dependent on the type of HRT (increased risk if the HRT contains norethisterone) and duration of therapy (62-65). Due to significant hormone sensitivity, BC development and progression involves dynamic alterations to estrogen, progesterone, and HER2/neu receptors (66, 67). Tumor subtypes that express estrogen and/or progesterone receptors are classified as hormone receptor (HR) positive or HER2/neu receptor positivity as HER2+ (absence of receptors is termed triple-negative) (67, 68). Knowledge of the receptor status is crucial for selecting hormonal/endocrine therapies with receptor-specific action (69).

Similar to breast tissue, both benign and malignant thyroid tissue are highly responsive to circulating estrogen (Fig. 1) (70). Indeed, elevated circulating sex hormone levels are associated with TC (71, 72). Hyperestrogenism (elevated endogenous estrogen) during reproductive years is associated with an increased prevalence of TC in women of reproductive age; however, HRT or other exogenous estrogen exposure are not linked to TC (72-74). As the use of hormonal contraceptives has steadily increased, its connection to BC and TC development is under debate (73, 75-79). Additionally, estrogen may serve as a link between the co-occurrence of autoimmune thyroid disorders and BC, which predominantly affect women (80). Immune tolerance and the development of autoimmunity is largely controlled by the AIRE gene (81); estrogen is a key regulator of this gene, and reduced activity from elevated estrogen contributes to autoimmune susceptibility (81-85). Overall, sex hormones, primarily estrogen, appear to have a connection to not only BC, but also thyroid dysfunction and malignancy.

Obesity Endocrine Link

In parallel with rising BC and TC incidences, obesity has risen 11.9% among adults from 1999 to 2018 (86). Body weight and fat composition in the setting of obesity are associated with both BC and TC risk (87-93). Perspectives on the causes and impacts of obesity have become increasingly endocrine-focused in recent decades (94). Many hormonally driven physiological changes—including adipocyte aromatase activity, aberrant chemokine signaling, low-grade inflammation, and metabolic alterations—are linked to obesity and are associated with BC and TC (90, 95, 96).

Elevated circulating estrogen from adipocytes may contribute to an increase in BC and TC risk (94). Postmenopausal women produce significant levels of estrone, estradiol, and free estradiol from aromatase-dependent sterol conversion in adipocyte tissue (97-99). Obesity is also associated with enhanced macrophage cyclooxygenase-2 (COX2) expression, which further promotes adipocyte-dependent estrogen production and elevated circulating estrogen (100-102). Obesity-related hypothyroidism reduces serum sex hormone-binding globulin (SHBG) and elevates free estradiol and testosterone (subsequently converted to estradiol by aromatase enzymes) (103-105). This apparent rise in estrogen due to high adipocyte accumulation is connected to BC and TC risk in postmenopausal women (71, 99, 104, 106, 107). Obesity-related changes to tissue-specific and circulating sex hormones support obesity as a potential hormonal mediator between thyroid and BC.

Beyond their role in postmenopausal estrogen production, adipocytes are hormonally active cells that produce and respond to numerous adipochemokines (adipokines). Adipokine dysregulation alters a variety of physiological processes—feeding psychology, inflammatory equilibria, and dysmetabolic syndrome—and is associated with BC and TC risk (108, 109). Leptin is a peptide hormone that signals satiety upon binding to ventromedial hypothalamic nuclei cells and is overproduced by adipocytes in obesity (110). Binding of leptin in nonphysiologic target tissues promotes cellular proliferation and carcinogenesis (111, 112). Proinflammatory adipokines—resistin, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-18 (IL-18), CXCL5, and CCL2—are also overproduced in obesity (109, 113). These signaling molecules promote BC and TC development through recruitment of cancer-associated fibroblasts (CAF), microenvironment remodeling, and direct cellular effects (109, 114-117). Finally, metabolism-altering adipokines—lipocalin-2, CXCL5, resistin—promote hyperinsulinemia and insulin resistance and directly interact with thyroid and breast tissue to promote metabolic changes and carcinogenic processes (118-124). Considered together, obesity alters physiological functioning of many adipocyte signaling molecules with notable impact on the breast and thyroid.

Aberrant adipokine signaling in obesity causes alterations in endocrine metabolism and energy homeostasis. Obesity gives rise to a global low-grade inflammatory phenotype due to immune remodeling of adipose tissue and elevated proinflammatory cytokines (125). Alongside chronic inflammation, metabolism-altering adipokines in obese states detrimentally affect energy utilization in many organs, resulting in metabolic syndrome, hyperinsulinemia, and insulin resistance (126). Elevated insulin levels and cellular resistance to insulin are associated with the development of BC and TC (127-130). Insulin-like growth factor-1 (IGF-1) signaling, which is critically integrated within hypothalamic-pituitary development of the breast and thyroid, is also altered in obese states, and elevated serum IGF-1 is associated with BC and TC risk (131-134). Aberrant IGF-1 signaling causes excessive activation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) pathways in breast and thyroid cells, leading to proliferation and migration of cancerous cells; several reviews are dedicated to describing the cellular changes that occur due to this disruption (133, 134). The interplay between obesity, hormones, and metabolic dysfunction alongside cancer risk is an active field of research.

Endocrine-Disrupting Chemicals

Endocrine-disrupting chemicals (EDC) are a class of environmental toxicants that interfere with hormonal pathways (135, 136). Estrogen-mimetic EDCs, xenoestrogens, effectively alter physiological estrogen signaling. Bisphenol A and genistein are well-established estrogen-mimetic, thyroid-disruptive EDCs associated with increased risk of BC and TC (137-142). Many additional chemicals, such as biphenyl ether flame retardants, polychlorinated biphenyls, phthalates, polyfluoroalkyls, and organo-pesticides, have thyroid-disrupting effects with TC risk (143). As previously described, thyroid endocrine disruption is associated with BC development; indeed, polychlorinated biphenyls, dioxins, and other thyroid-disrupting EDCs are associated with increased risk of BC (144, 145). The landscape of EDC disruption is complex and continually expanding, and the apparent effects of EDCs in thyroid and breast carcinogenesis give credence to a hormonal connection between these malignancies.

Stimulatory Capacity of Thyroid and Sex Hormones

Thyroid Hormones and Breast Cancer

Thyroid hormones elicit genomic actions by binding to nuclear receptors that subsequently exert transcriptional effects on target cells (146). There are multiple splice variants of the thyroid hormone nuclear receptor genes, TRα and TRβ, including TRα1, TRα2, TRβ1, TRβ2 (146). T3 has significant bioactivity on 3 of these receptor isoforms—TRα1, TRβ1, TRβ2—and induces expression of genes associated with cell growth and movement (147). Thyroid hormones also interact with target tissues independent of transcriptional action via the membrane-bound integrin αvβ3 protein (148). Both T3 and T4 exert cellular effects via the integrin αvβ3 pathway; T3 and T4 binding to the S1 subunit activates the PI3K/Akt pathway, and T4 binding to the S2 subunit activates MAPK/ERK1/2 pathways (27, 149, 150). Activation of the integrin αvβ3 protein is associated with cellular migration, proliferation, and angiogenesis via the MAPK and ERK1/2 pathways (148, 151-153). TH-mediated activation of integrin αvβ3 is implicated in protumorigenic features of many cancers, including glioma, ovarian, oral, colorectal, and BC cells (154-159).

All thyroid hormone nuclear receptor splice variants—TRα1, TRα2, TRβ1, and TRβ2—have been detected in BC cells (160-162). While not inducible by T3, TRα2 downregulates TRα1 such that high expression of TRα2 reduces the actions of TRα1 (163). In BC, TRα2 expression is a positive prognostic marker compared with diminished disease-free survival among TRα1-expressing BC tissue (164-166). Contrary to TRα1, TRβ1 expression in BC is associated with protective effects in vitro and in vivo through regulation of genes associated with aberrant cellular growth (161, 167-171). While TRβ2-specific studies and discussion are limited, Davidson and Gillis et al provide a comprehensive review of the antitumor effects of the TRβ protein class on solid tumor oncogenesis, particularly through JAK-STAT and PI3K pathway inhibition (172). Within BC studies, TRβ protein activation via T3 is associated with attenuation of JAK-STAT and RUNX2 signaling pathways, leading to reduced metastatic potential (173, 174). Taken together, these findings suggest that T3 has both pro- and antitumorigenic effects on breast tissue through transcriptional action, although the dominant effect is not well understood (Fig. 2).

Figure 2.

Hormone signaling crosstalk between thyroid and breast. Thyroid and sex hormone signaling is driven either by interactions with membrane receptors (eg, MCT8/10, integrin avb3, TSHR, EGRF, IGFR, or ER among others) or direct access to the cytoplasm or the nucleus. The mechanisms of action of these hormones are often overlapping between thyroid and breast cells, ultimately resulting in transcriptional changes at the nucleus. While genomic actions involve the interaction of the thyroid (T3 or T4) or sex hormones (eg, estrogen) to nuclear receptor (TR or ER), they can also regulate target tissues by transcription-independent mechanisms. Nongenomic actions are initiated in the cytoplasm and include the activation of signal transduction kinases in the MAPK or PI3K/AKT pathway prior the stimulation of TR and ER. Thyroid hormones and estrogen also display cytoplasmic and nuclear crosstalk through MAPK-induced estrogen receptor modification, shared nuclear coregulators (eg, NCOA1, SMART, and NCOR1), and hormone response element ambiguity. Figure created with BioRender.com.

Thyroid hormones also influence BC risk via integrin αvβ3 independent of genomic activity. Primary cell cultures of human BC express epithelial integrin αvβ3, which is associated with lymph node and distant metastasis (175-178). T4 enhances ERK1/2 activity and promotes PD-L1 expression, presumably through integrin αvβ3 binding, and T3 binds and activates integrin αvβ3 to promote cell migration via downstream actin pathways and PI3K activation (Fig. 2) (33, 179, 180). However, despite these observations, the impact of thyroid dysfunction within the multistep metastatic process in BC is not well understood (177, 178). In addition to the physiologically abundant thyroid hormones, T3 and T4 metabolism yields a variety of bioactive metabolites—notably reverse triiodothyronine (rT3), 3,5-diiodothyronine (3,5-T2), 3-iodothyronamine (3T1AM), and tetraiodothyroacetic acid (tetrac) – with varying effects on integrin αvβ3 (181). 3,5-T2 and rT3 bind and activate integrin αvβ3, leading to proliferation in breast and ovarian cancer cell lines (182-184). Cancer cells in general, including BC cells, overexpress the deiodinase-3 enzyme for conversion of T4 and T3 into rT3 and 3,5-T2 respectively, which promote local protumor conditions (152, 185, 186). 3T1AM and tetrac counteract BC invasiveness—3T1AM via trace amine-associated receptor 1 (TAAR1) activation, and tetrac via inhibition of integrin αvβ3 (187-189). In particular, tetrac has notable antitumorigenic effects on BC cells by reducing cellular proliferation, angiogenesis, and PD-L1 activity and increasing apoptosis, suggesting promising therapeutic action (33, 189-192).

Sex Hormones and Thyroid Cancer

Several studies and reviews report estrogen’s effects on TC development and progression (70, 193-195). Estrogen binds to 2 nuclear receptors—ERα and ERβ (196). Both ERα and ERβ are overexpressed by TC cells with estrogen-activated ERα inducing proliferation, angiogenesis, and migration in TC cells (197-203). In contrast, ERβ activation is associated with antiproliferative properties with a higher ratio of ERα to ERβ thought to influence estrogen’s dominant effect on thyroid tumorigenesis (204-207). ERα can be localized to either the cell membrane/cytoplasm or the nucleus, with differential cellular effects upon activation (208). Estrogen stimulation of membrane-associated ERα impacts many cellular pathways within TC cells with notable activation of AKT/mTOR, MEK1/2, and MAPK pathways (Fig. 2) (208-213). Nuclear activity of ERα in thyroid cells, alongside epigenetic alterations and chromatin decondensation, induces transcription of proliferation-associated proteins and regulation of PPARγ transcriptional activity (208, 209, 214-218). The cellular effects of membrane-associated and nuclear ERα are significantly interconnected; Manole and colleagues provide a detailed review of these cellular actions and overlap in thyroid cells (208). Finally, estrogen receptor signaling also has an indirect proliferative effect on thyroid cells by increasing thyroid cell sensitivity to TSH signaling (202).

Estrogen’s apparent activation of MAPK signaling pathways in TC cells has implications for iodine avidity and RAI therapy. BRAF^V600E− and fusion-driven differentiated TCs display marked MAPK and MEK/ERK activation that alters epigenetic protein activity and sodium-iodine symporter (NIS) promoter transcription (219). Therefore, it stands to reason that MAPK activation via estrogen stimulation in TC cells may account for reduced NIS expression in estrogen-stimulated TC cell lines (208, 220). Few confirmatory reports of this phenomenon exist, yet nuclear receptors similar to estrogen receptor affect iodine avidity. Particularly, estrogen-related receptor gamma (ERRγ), a protein in the nuclear receptor superfamily, enhances MAPK signaling and causes reduced NIS expression, providing indirect evidence of estrogen nuclear receptor involvement in NIS expression (221). Considering the importance of NIS expression for RAI therapy in TCs, the interactions between estrogen signaling and iodine avidity must be further defined.

Progesterone and androgens (ie, testosterone and dihydrotestosterone) also interact with nuclear receptors to elicit cellular responses. As mentioned, progesterone receptor (PR) positivity is an important prognostic factor in BC. While progesterone is expressed in some TC tissue, studies have not shown a significant correlation between progesterone receptor status and TC progression (200). Similarly, androgen receptors (Ars) are expressed in TC tissue, yet there is little consensus as to the oncologic effects of AR activation. Some studies report an association between AR expression and capsular invasion and extrathyroidal extension, while others suggest a protective role via growth arrest and reduction of PD-L1 expression (222-224). Interestingly, testosterone exhibits a direct protumorigenic effect on TC progression and severity via attenuation of tumor suppressor genes (225, 226). More research is needed to further define the potential role of progesterone and androgen signaling in TC tumorigenesis and progression.

Thyroid and Steroid Hormone Nuclear Receptor Cross-Reactivity and Crosstalk

Sex steroids and thyroid hormones bind to nuclear receptors belonging to a structurally related protein superfamily. Estrogen and progesterone interact with steroid nuclear receptors to allow for binding to estrogen response elements and subsequent gene transcription (227). Thyroid hormones interact with nuclear receptors that heterodimerize with retinoid X receptors (RXR) and bind to thyroid response elements to lift epigenetic restraints on gene transcription (227). These nuclear receptors regulate gene transcription alongside numerous gene coactivators and corepressors; many of these coregulators—such as SRC-1/NCOA-1, NCOR-1, SMRT, retinoid receptor proteins—are shared between steroid and RXR-heterodimeric thyroid nuclear receptor complexes (227, 228). Additionally, hormone response elements—including estrogen and thyroid response elements—have low binding specificity within the nuclear receptor superfamily such that hormone-specific nuclear complexes have overlapping binding potential with broad hormone response elements (229, 230).

Hormone nuclear receptor crosstalk has implications for BC and TC development and co-occurrence. Indeed, mutations in sex hormone and thyroid hormone nuclear receptor coregulators, like NCOR-1, serve as drivers for some BC and TCs (231-233). Shared coregulators regulate sex and thyroid hormone-induced transcription, which may influence aberrant cellular processes and mutual oncogenesis (234, 235). In BC cells, thyroid hormone and estrogen signaling also display significant crosstalk through promoter cross-reactivity, both with estrogen-induced thyroid hormone response element-binding and thyroid hormone-induced estrogen response element-binding (236-240). Additionally, nongenomic thyroid hormone action via integrin αvβ3 influences cellular localization and activity of estrogen receptors by activating MAPK-dependent phosphorylation of ERα nuclear receptors (241). Cellular thyroid hormone signaling directly impacts estrogen-related therapeutics in BC cells through shared nuclear coregulators, promoter ambiguity, and nongenomic overlap (242-246). Considering analogous structural and functional features within the nuclear receptor superfamily, research into the cellular overlap of estrogen and thyroid signaling is important for both a greater understanding of breast-thyroid interplay as well as for the anticipation of unintended effects of hormonal therapies.

Therapeutic Considerations

Thyroid Hormone Signaling Targets in Breast Cancer

Thyroid-based therapeutics provide potential adjuvant options for the treatment of BC (22). Considering the genomic actions of thyroid hormones, thyroid hormone nuclear receptor isoforms present several therapeutic targets. Dronedarone has been shown to antagonize the protumorigenic activity of TRα1 nuclear receptors with cytotoxic effects on BC cell lines (247). The antiproliferative effects of TRβ activity have been targeted with many TRβ-specific agonists over the past few decades for metabolic and musculoskeletal disorders (248). Resmetirom has proved most successful with recent FDA approval for nonalcoholic fatty liver disease; such agents may have efficacy in BC (249). Considering the role of retinoic acid receptors within sex and thyroid hormone nuclear crosstalk, retinoic acid and retinoid receptor agonists are being considered for adjuvant therapy in BC (250-252).

Integrin αvβ3 inhibition presents a nongenomic therapeutic target for reducing the proliferative effects of thyroid hormones on BC cells. Tetrac displays considerable integrin αvβ3 antagonism with broad anticancer properties. So far, in vitro and in vivo evidence suggests that tetrac has the potential to reduce proliferation and angiogenesis of BC cells (191, 192, 253). Synthetic inhibitors of integrin αvβ3, like cilengitide, may prove efficacious in BC despite recent failures in glioblastoma clinical trials (254). With particular interest in receptor-targeted radionuclides, integrin αvβ3 radionuclides are also being explored as theragnostic agents for BC and other cancers (255). Despite documented action of T3 on breast cell integrin αvβ3 proteins, T3 replacement of T4 supplementation has been anecdotally used to reduce integrin αvβ3 activity in other cancer cells and may be applicable to BC (152). Integrin αvβ3 signaling has garnered significant attention in a variety of cancers, and future work may translate laboratory findings to clinical practice for BC and TC.

Sex Hormone Signaling Targets in Thyroid Cancer

The effects of estrogen and androgens on TC cells suggest potential benefit of sex hormone targeted therapies for the treatment of hormone-responsive TC. ERβ could be therapeutically activated to elicit antitumorigenic response in TC. Erteberel, a selective ERβ agonist, is currently under investigation for the treatment of schizophrenia and has gained recent attention for use in glioblastoma (256). Similarly, ERα antagonists may prove efficacious for reducing proliferation in TC. However, no studies to our knowledge have investigated the potential of repurposing estrogen receptor antagonists (ie, fulvestrant) or selective estrogen receptor modulators (ie, tamoxifen, raloxifene) in ERα-positive TC. While a study by Hoelting and colleagues shows in vitro and in vivo suppression of thyroid function and proliferation by tamoxifen, it is unclear whether selective estrogen modulators would produce unintended effects compared with full estrogen antagonists (257). Finally, androgen antagonists are successfully utilized in androgen-responsive cancers, like prostate cancer, yet greater understanding of androgen signaling in the thyroid is required before androgen-targeted therapeutics should be investigated for repurposing in TC.

Targeting NIS Expression in Breast and Thyroid Cancer

In TC, iodine avidity can be therapeutically induced by tyrosine kinase (TK) inhibitors (219, 258). Vermafenib, a BRAF^V600E-specific inhibitor, and selumetinib, a MEK1/2 inhibitor, restore iodine avidity in RAI-refractory TC by attenuating RAS-RAF-MEK-ERK signaling (259, 260). With likely effects of estrogen receptor and ERRγ on MAPK signaling, estrogen antagonists and selective estrogen receptor modulators may restore iodine avidity in estrogen-responsive TCs similar to TK inhibitors. Indeed, ERRγ inverse agonists have been shown to increase NIS expression in anaplastic TC cell lines and may be clinically efficacious for restoring iodine avidity clinically (221, 261).

While conventionally used to treat TC, RAI may be clinically beneficial for treatment of advanced BC. Malignant breast tissue, including triple-negative BC, expresses NIS proteins and functionally uptakes iodine (262, 263). Developing therapeutics that differentially increase NIS expression in breast tissue over benign thyroid tissue could spare a healthy thyroid from breast-targeted RAI (258). Retinoic acid has been shown to increase functional NIS expression in BC cells and TC cells while reducing NIS activity in nonmalignant thyroid cells (264, 265). Further exploration of such therapeutics may allow for practical RAI therapy in the setting of advanced BC.

Metabolic Signaling Targets in Breast and Thyroid Cancer

Obesity-related pathophysiology promotes BC and TC, and therapeutics targeting these alterations have garnered recent attention. Adipocyte aromatase activity in obesity has notable effects on circulating estrogen that can be targeted by aromatase inhibitors (ie, letrozole and anastrozole). Such agents show significant clinical efficacy in postmenopausal patients with BC, but no studies have explored their use for TC (266, 267). Adipokines present several additional therapeutic targets. For example, anti-lipocalin-2 and anti-IL-6-receptor antibodies reduce BC metastasis in murine models (120, 268). However, the intersection of adipokines, metabolism, and BC/TC risk is extremely complex, contributing to mixed clinical trial results and unintended side effects. To the surprise of academic and industry investigators, studies evaluating efficacy of diabetes medications, like metformin, as adjuvant agents for BC treatment have reported little clinical benefit; however, there are data supporting an antitumorigenic effect of metformin in TC (269, 270). Similarly, teprotumumab, an anti-IGF-1 receptor antibody, achieved greater clinical success for the treatment of thyroid eye disease than as a cancer therapeutic (271). Clinical trials for many of these targets are ongoing, and future research is needed to better explain the cellular and endocrine consequences of obesity in relation to breast and thyroid tumorigenesis.

Conclusions

Numerous hormones, including thyroid, reproductive/sex, adipocyte, and hormone-like EDCs, influence BC and TC pathogenesis. As endocrine organs, the breast and thyroid are responsive to their respective hypothalamic-pituitary axes as well as hormones from the broader endocrine physiologic pathways. While many therapeutic opportunities present from this hormonal crosstalk, one must be cognizant of the potential unintended consequences of clinical therapeutics directed at one organ system that may negatively impact the other. For example, with the increased use of TK inhibitory therapy to re-sensitize TC to RAI therapy, clinicians and researchers must also consider the potential impact of TK inhibitor therapy on NIS expression in breast tissue and the potential impact of increased radiation burden to the breast. Future collaborations and discussions are needed to improve our understanding of the interconnected signaling pathways between the breast and thyroid systems. Doing so may enable the development of novel hormonal treatment strategies, reduce unintended physiological disruption, and limit adverse effects of conventional cytotoxic therapy.

Glossary

Abbreviations

3,5-T2

3,5-diiodothyronine

3T1AM

3-iodothyronamine

AKT

protein kinase B

AR

androgen receptor

BC

breast cancer

EDC

endocrine-disrupting chemical

ERα/β

estrogen receptor α/β

ERRγ

estrogen-related receptor gamma

FSH

follicle stimulating hormone

HPT

hypothalamus-pituitary-thyroid

HRT

hormone replacement therapy

IGF-1

insulin-like growth factor 1

IL-

interleukin

LH

luteinizing hormone

MAPK

mitogen-activated protein kinase

NIS

sodium-iodine symporter

RAI

radioactive iodine

rT3

reverse triiodothyronine

T3

triiodothyronine

T4

thyroxine

TC

thyroid cancer

tetrac

tetraiodothyroacetic

TK

tyrosine kinase

TRα/β

thyroid hormone receptor α/β

TSH

thyrotropin (thyroid-stimulating hormone)

TSHR

thyroid-stimulating hormone receptor

Supporting Grants/Fellowships

National Institutes of Health, R01 CA214511, Children’s Hospital of Philadelphia Intramural Frontier Grant

Disclosures

S.H., V.C.M., J.A.B., J.L., P.C., and J.A.B. have nothing to declare. A.T.F. is on the Board of Directors for the American Thyroid Association.

Authorship Contributions

S.H., J.L., A.J.B., and A.T.F. devised the project. S.H. wrote the manuscript, V.C.M. and A.T.F. created the figures, and V.C.M., J.A.B., P.C., A.J.B., and A.T.F. provided support and critical review. S.H., V.C.M., J.A.B., J.L., P.C., A.J.B., and A.T.F. discussed the review and provided editorial feedback of the manuscript.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.