|Year : 2020 | Volume
| Issue : 1 | Page : 1-7
The role of estrogen receptors α, β, γ in oral squamous cell carcinoma and a comparative perspective of squamous cell carcinoma
Eesha Thakare1, Minal Chaudhary2, Amol Gadbail3
1 Department of Oral Pathology and Microbiology, Nanded Rural Dental College, Nanded, Maharashtra, India
2 Department of Oral Pathology and Microbiology, Sharad Pawar Dental College and Hospital, Sawangi, Wardha, Maharashtra, India
3 Department of Dentistry, Indira Gandhi Medical College and Hospital, Nagpur, Maharashtra, India
|Date of Submission||26-Jan-2020|
|Date of Acceptance||26-Feb-2020|
|Date of Web Publication||16-May-2020|
Dr. Eesha Thakare
Shiv Multispeciality Dental Clinic, Akshay Plaza, Opposite Janata Bank, Jatharpeth, Akola - 444 005, Maharashtra
Source of Support: None, Conflict of Interest: None
The “nuclear receptors” (NRs) belong to the huge group of transcription factors, triggered with the help of diverse signal molecules. Various physiological (or pathological) conditions responding to metabolite, hormonal, and nutrient signals lead to the activation of specific gene expression with the help of large number of members of NR superfamily. The role of hormone estrogen as an oncogenic agent is well illustrated in hormone-sensitive carcinomas that include ovarian, colon, endometrial, prostate, lung, and breast. This is the first review on oral squamous cell carcinoma (OSCC) pertaining to Estrogen receptors (ER) like α, β and γ study published in PubMed. For hormone ligand action in head and neck carcinomas (HNCs) specifically, experiments in vivo and in vitro studies support a probable biological mechanism. As per the search in PubMed (search words ERs, OSCC, HNCs), since the first article till date, a review pertaining to the existence and role of ERs in OSCC was formulated since 1981 till 2018. This is the first review on receptor level genomics in OSCC for three ERα, β, and γ. We have also discussed ERγ, which has been reported in very few reports. The prognostic significance of ERα, β, γ in comparison with other squamous cell carcinoma is tabled.
Keywords: Estrogen receptors α, β, and γ, Oral Squamous cell carcinoma, Squamous cell carcinoma
|How to cite this article:|
Thakare E, Chaudhary M, Gadbail A. The role of estrogen receptors α, β, γ in oral squamous cell carcinoma and a comparative perspective of squamous cell carcinoma. Indian J Oral Health Res 2020;6:1-7
|How to cite this URL:|
Thakare E, Chaudhary M, Gadbail A. The role of estrogen receptors α, β, γ in oral squamous cell carcinoma and a comparative perspective of squamous cell carcinoma. Indian J Oral Health Res [serial online] 2020 [cited 2020 Sep 30];6:1-7. Available from: http://www.ijohr.org/text.asp?2020/6/1/1/284444
| Introduction|| |
The “nuclear receptors” (NRs) belong to the huge group of transcription factors, triggered with the help of diverse signal molecules such as retinoic acid, vitamins, thyroid hormone, steroids, and numerous other metabolites. Although a unique subset of the NRs still remains “orphans” (ONRs) still with an undefined endogenous ligand. These NRs, when activated along with a large number of cofactors, activate transcription of genes controlling cell reproduction, development, proliferation, and diverse metabolic phenomena. The coordination of NRs and associated cofactors constitute a suitable functional control mechanism of energy pathways contained by the cells. Various physiological (or pathological) conditions responding to metabolite, hormonal, and nutrient signals lead to the activation of specific gene expression with the help of large number of members of NR superfamily.,
Hormones move through blood and converse with cells which lay distant from the parent organ. They function as signaling molecules acting on target cells, i.e., cells that express specific receptors. They perform to synchronize the growth, metabolism, and differentiation between cells in different organs and tissues. One such hormone is estrogen. Growing evidence suggests that the production of estrogen along with signaling can be cell and tissue-specific. Along with acting as a female sex hormones in development and function of gonadal organ, it performs vital functions in extragonadal tissues such as bone, brain, liver, heart, and muscle in accordance with treatment which are presently been valuated in clinical trials for numerous age-related diseases.
The role of hormone estrogen as an oncogenic agent is suitably illustrated in classical and non-classical hormone-sensitive carcinomas that include ovarian, colon, endometrial, prostate, lung, and breast. The location of estrogen receptors (ERs), in cytoplasm and nucleus of tumor cells, makes possible the tumor to promote transcriptional directive of genes involving in cell proliferation and survival. With growth factor pathways, estrogen elucidates a nongenomic crosstalk, including fibroblast growth factor, epidermal growth factor (EGF), and insulin growth factor. Hence, in numerous cancers, E2 pathway is said to promote tumorigenesis.
The receptors of estrogen act by two pathways:
- Novel cell surface membrane receptors (GPR30 and ER-X)
- Classical NRs (ER alpha [ERα] and ERβ).
The cell and tissue-specific mode of action of estrogen along with its receptors often contribute to healthy aging and deviating outcomes of estrogen therapy in aging-associated diseases. Energy homeostasis is controlled by the “estrogen-related receptors” (ERRs) which are significant members belonging to the ONRs' family.
The ERRs share significant sequence homology in “ligand binding domain” (LBD) and about 68% sequence homology in “DNA binding domain” (DBD) with ER. These are named as orphan NRs because there is no natural ligand detected binding them. The ERR family includes three members ERRα, ERRβ, and ERRγ that are closely related. Among these, ERRα and ERRγ participate considerably as both repressor and transcriptional activator in metabolism and cancer. The lesser studied “ERRβ” expression is missing during cancer progression, indicating its the role in tumor suppression.
| Structure of Estrogen-Related Receptor|| |
The ERR subfamily consists of three isoforms, specifically “ERRα” (NR3B1), “ERRβ” (NR3B2), and “ERRγ” (NR3B3). They first identified ERRα (45.5 kDa, 423a. a.) and EERβ (56.2 kDa, 508a. a.) in a process where they screened the human male gonad cDNA library. This was carried out with a probe whose synthesis was based on the DBD sequence of ERRα cDNA and ERα. A dissimilar methodological method led to the discovery of the third member after 10 years, named as ERRγ (51.3 kDa, 45a. a.)., Numerous splice variants of human ERRs were discovered but their physiological role is still not clear. Despite that ERRs share sequence and name with ERs, they do not bind to natural estrogens. Although the subsistence of functional crosstalk inbetween ERs and ERRs cannot be overlooked, a significant correlation was seen with ERRα and ERRs, which also showed a distinct genomic functions and signature.
As the members of superfamily of the NRs, ERRs are characterize by a conserved functional and structural organization including various domains and ligands.
The sequence analysis carried out with receptor isoforms such as ERRα, ERRβ, and ERRγ revealed a dissimilar sequence homology with regard to the domains: In that, all three members show different sequence identity like that of ERRβ and ERRγ show 73%, while at DBD show 93%–98% sequence identity; with regard to the LBD, the ERRα and ERRβ are less associated (57%). The next domain of ERRβ and ERRγ shows significant amount of sequence identity with respect to A/B domain (60%) and around 63% between ERRα and ERRγ.
As per the discovery, ERR isoforms show strong correlation to ERα and ERβ as compared with the other members of the NR superfamily. Especially, the investigation of individual domain demonstrate 36% LBD homology and for DBDs around 70% homology of ERRα and ERα, thus stating the probable rationale for the dearth of ERRα response to ER ligands.
| Estrogen in Health and Function|| |
Structure and domain of estrogen alpha in health and carcinogenesis:
The first ER discovered by Jensen (1958) was named ERα. ER showed 6 distinct functional domain: A, B, C, D, E and F functioning as: DNA binding, transcription activation, ligand binding and dimerization.
The role of ERRα is significant in embryonic development and also there is remarkable rise in its expression in the nervous system, heart, and skeletal muscles. The physiologic key role of ERRα is as an energy sensor that controls the mechanism of energy requirement for cellular adaptation along with is associated with the prime function in responding to multiple metabolic stress conditions. This explains the remarkable presence of ERRα in high-demand energy tissues such as brown adipose tissue and muscles. Loss of expression of activated ERRα in cells, fail to make adequate energy at peak demand instants. The regulation of energy metabolism in adipose tissue seems to be governed by ERRα which promotes the formation of adipocytes by differentiation of mesenchymal stem cells. ERRα increases oxidative phosphorylation, tricarboxylic acid cycle, β-oxidation, mitochondrial biogenesis, and lipid absorption. ERRα also influences the differentiation of intestinal epithelial cells, T cells, myocytes, and osteoblasts. A study proved the important role in embryogenesis for bone development especially during bone formation by intramembranous and endochondral ossification and also in metabolism process., They also found the mRNA expression in murine bone cells and also in human osteoblasts (primary).
The mode of action on transcriptional coactivators of ERRα (PGC-1α and PGC-1β) brings about the integration of the signals targeted on energetic and nutritional status and this drives the expression of genes controlling the oxidative metabolism, mitochondrial biogenesis, and gluconeogenesis. ERRα behaves as a potent transcriptional activator once either of PGC-1α or of PGC-1β is instigated. The interactions inbetween PGC-1α and β regulate the ERRα activity. ERRα gene expression is also modulated by PGC-1s. This leads to higher levels of ERRα mRNA in tissues having increased levels of PGC-1α and β. The oncogenic signals in cancer cells directly targets the “PGC-1s/ERRα” complex which influences metabolic programs that supports cell proliferation and growth. Furthermore, PGC-1α gene suppression by hindering oxidative phosphorylation and mitochondrial biogenesis leads to reduced rate of metastasis.
Various observations support these findings such as:
- The key regulator PGC-1α along with promoter binds to ERRα, which regulates the vascular endothelial growth factor that acts chiefly in regulating angiogenesis and tumor invasion,
- ERRα cooperates with hypoxia inducible factor (HIF) in induction of the cancer metabolic reprogramming directed toward the metastatic-promoting glycolytic state and also with HIFα/β heterodimer is involved in angiogenesis and cell migration,,,
- ERRα along with PGC-1α, controls WNT11 expression which in turn with β-catenin regulates the migratory ability of cancer cells.
ERRα target genes have now been identified by various functional genomic studies to play an important role in the process of tumor vascularization, invasion, and migration.
Thus, this explains the key role of the ERRα in numerous processes that direct tumor progression and aggressiveness.,,
Structure and domain of estrogen beta in health and carcinogenesis
ERβ is the second ER, cloned successfully from prostate cDNS, and from human testis. Ogawaet al. cloned ERβ from human being which was reported to comprise of 530 amino acids. It is located on chromosome 14. The ERβ comprises of the molecular structure with distinct function domain: A to F.
ERβ receptors predominantly were expressed in organs not associated with reproduction. The genetic expression of estrogen in the different organs is defined by the balance between the concentrations of their receptor subtypes and the recruitment (or lack of recruitment) of the coactivator and corepressor factors for each subtype.
ERβ can activate transcription of ERE possessing promoters in a ligand-independent manner. High affinity for E2 is shown by ERβ containing a single binding component. Contrary to ERα, an overall increase in trancriptopnal activity is appreciated as AF-1 functions as repressor domain whereas the AF-2 domain of ERβ acts independently within the receptor. Cell nuclei of human tissues, by immunolocalization of ERβ, demonstrated its presence in the gastrointestinal tract, cardiovascular and immune systems, central nervous system, kidneys, urogenital tract, and lungs and thus indicated the role of receptor ERβ in estrogen action. Elevated ERβ receptor expression in the osteoblast and in the differentiation of osteoblast (in vitro) ropes the significance of this “bone ER” in osteoporosis. The role of modulator ERα receptor-mediated gene transcription in the urogenital tract, along with the overall cellular sensitivity of E2 was reduced by ERβ suggesting its protective role against carcinogenesis and hyperproliferation.
Structure and domain of putative estrogen gamma in health and carcinogenesis
The new putative ER (pER) or ER-gamma ( first identified in 1998) was purified and isolated from mouse liver. High specificity for E2, estrone, and estriol was showed by the 84 kDa heterodimer, which was a serine phosphatase along with dissociation constant of Kd = 0.7 nmol/l along with binding sites for E2 at saturation 0.746 pmol/mg of pER protein. pER was detected by immunohistochemical analysis in the endometrial, ovary and mammary tumors, nonreproductive organs (vascular, hair, skeletal, retina, and neural cells), and prostate. The involvement of pER in estrogenic signaling pathway, may evoke a superfluity of estrogenic action in nonreproductive organs, suggesting its role in carcinogenesis of tissues showing response to estrogen.,
| Estrogen and Oral Squamous Cell Carcinoma|| |
Estrogens can modulate the epithelial maturation process in specific target organ. During menopause, the drop in estrogen levels seems to influence the oral epithelial maturation process, resulting in an epithelium which becomes atrophic, thin prone to inflammatory changes. In postmenopausal women, decrease in estrogens may correlate with the oral epithelium (atrophic in nature) and replacement of this insufficiency by means of HRT may reinstate normal epithelial proliferation and maturation. Elevated levels of ERα are seen in the vascular endothelial, SMCs, and other parts of oral tissues, while ERβ was expressed in gingival and buccal epithelium of oral mucosa.
As per experimentsin vivo andin vitro studies for head-and-neck carcinomas (HNCs) specifically, a reasonable biological scheme for hormone ligand action can be elucidated. As per the search in PubMed (Search words - estrogen receptors, head and neck carcinoma (HNC) and Oral squamous cell carcinoma (OSCC), since the first article till date, a systematic review pertaining to the existence and role of estrogen receptors in OSCC was formulated [Table 1]. Molteni et al.'s first reported Estradiol (E2) receptor-binding protein presence among 4/6 SCC in the oral cavity. As per the ER assays, 2.7% (2/75) were positive, 89.3% (67/75) were negative, and 8% (6/75) were borderline. As per Bassalyk et al., the ability of receptor cytoplasmic proteins to bind androgens was more frequently identified in squamous cell carcinoma (SCC) than in leukoplakia whereas the ER situation was reverse. Somers et al., successfully demonstrated in nude mice, that estradiol treatment promotes the expansion of laryngeal tumors. Kushlinskiĭ et al. confirmed a positive correlation between detection rate and the mean values of androgen and ERs and sex, age, disease stage, type of growth, and site of a tumor in patients of OSCC. They explained age-associated dependence on detection and levels of androgen and ERs in the leukoplakic foci of the oral mucosa. The presence of cytoplasmic ERs (50%) and oral mucosal squamous cell cancer (34.4%) was found in the foci of leukoplakia and with increase in mean levels. Ishida et al. studied cultured cell lines of varied SCC and primary human SCC, observed that the tumor cells showed high-level expression of ERβ. They proved that focal adhesion kinase (FAK) phosphorylation was reduced by tamoxifen (TAM), resulting in reduction in mitogen-activated protein kinase phosphorylation and extracellular signal-related kinase (Erk). The treatment carried out with TAM (ER antagonist) and not with estradiol (agonist) lead to observable time-dependent manner apoptotic cell death of SCC cells. The proliferation of SCC cells was repressed by the knockdown of ERβ by small interfering RNA. In addition, TAM was seen strongly inhibiting the invasion of SCC. These results proved that inhibition of ER may prove to be effective treatment in SCC and also in prevention of invasion and metastasis. A number of cofactors such as CREB-binding protein, NR corepressor, and steroid receptor coactivator 1 (SRC-1), all interrelate with ERs to control transcriptional activation or repression of target genes was proved by Ku and Croweshowed TAM treatment resulted in inhibition of stratified squamous epithelium-derived human cancer lines proliferation and cell cycle progression. They concluded that the SRC-1 in human SCC lines, is the principle molecular determinant of estrogen-mediated proliferation. Nelson et al. proved that OSCC is SERM and estrogen responsive and the resulting combination can regulate cell-matrix interaction, partially by altering integrin translation and expression. Thereby confirming the significant influence of these adjuvant therapeutics on growth. Lukits showed that ER and PGR are expressed in almost half of the examined tumors. He also demonstrated the presence of functional ER in cases (40.3%), with rare expression of solitary hormone receptor. The expression of hormone receptors showed positive correlation only with the laryngeal/hypopharyngeal group associated with a shortened survival. A study by Egloff et al., in 2009, proved nuclear ERα (ERαnuc) and EGFR expression were significantly raised in HNSCC tumors then to adjacent mucosa, while ERβnuc expression remain unchanged. With consideration to elevated tumor levels of ERαnuc and EGFR, patients had considerably decreased progression-free survival (PFS). While, elevated levels of ERβnuc, were not associated with decreased PFS alone or when combined with EGFR. A combined estrogen (E2) and EGF treatment significantly increased the Phospho-MAP kinase (P-MAPK) levels. All patients treated E2 and EGF, of HNSCC cells showed significantly increased cell invasion. Although compared to treatment with inhibition of these two pathways E2 and EGF showed reduced invasion compared to inhibiting either pathway alone, thus indicating that ER and EGFR together may have a role in development and disease progression of HNSCC.
|Table 1: Systematic review of estrogen receptors a and β as per PubMed search for head and neck squamous cell carcinoma and oral squamous cell carcinoma with prognostic significance|
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Colella et al. were the first to analyze androgen receptor (AR) and estrogens receptor alpha (ERα) mRNA by RT-PCR in HNC. AR transcripts showed reduced expression in OSCC specimens as compared to healthy tissues, whereas the expression of ERα transcripts appreciably improved in tumor samples. Eliassen et al. reported as specimen with tongue carcinoma to be negative for ER, HPV, progesterone receptor, p16, and HER-2. Marocchio et al. demonstrated that ERβ showed almost 40% positive expression by immunohistochemistry and AR only in 26% cases. ERα and Aromatase enzyme showed less expression. Chang et al. showed positivity in 43% (9/21) of malignant lesions for ERα by immunoreactivity, but it was absent in benign lesions. In the slow-growing SCC25 cell line, increased cell growth rate, ERα phosphorylation, and transcriptional activity was seen with elevated expression of FAK. And hence, ERα and FAK can serve as the therapeutic targets in OSCC treatment. Tiwari et al. demonstrated decreased level of expression after binding of tumor suppressor miR-125a to the 3'UTR of ESRRA. They observed in OSCC that elevated expression of miR-125a led to increased apoptosis, radically reducing the expression of ESRRA, and cell proliferation. They proved that the presence of the 3'UTR in ESRRA results in increased apoptosis and reduced cell proliferation in OSCC. Poorly differentiated OSCC tumors predominantly expressed ERβ as the prime ER subtype when compared with adjacent healthy mucosa of the tumor. Correlation of histological grade with varied expression patterns in OSCC may propose a significant role of ERβ in tumor (de-) differentiation was demonstrated by Doll et al. Tiwari et al. were the first to prove, in OSCC the subsequent rise in the level of ESRRA by genomic amplification of ESRRA, using TaqMan(®) copy number assay. siRNA facilitated invasion and accelerated apoptosis along with anchorage-independent cell growth and reduced cell proliferation after knockdown of ESRRA expression.
Grimm et al. demonstrated positive ERα expression in 4 oral precursor lesions (squamous intraepithelial neoplasia), i.e., 11% and in five OSCC specimens (11%). Mallery et al. assessed the performance of three complementary chemopreventives with respect to suppress OSCC tumorigenesis and gratuitous signaling. They tested chemopreventives such as fenretinide (vitamin A derivative), 2-methoxyestradiol (2-ME) (estrogen metabolite), and the humanized mAb to the IL6R receptor tocilizumab. The fenretinide (4-HPR) known to incite differentiation, apoptosis and invasion inhibits signaling proteins, 2-ME usually shows apoptosis, antiangiogenic properties, and the humanized mAb (TOC) shows reduction in IL6 signaling. OSCC tumor xenograft studies demonstrated prevention of significant tumor growth when treated with locally delivered, TOC + 4-HPR, TOC, and TOC + 4-HPR+2-ME. Notably, the most remarkable was when TOC + 4-HPR+2-ME treatment was administered, the final result was the smallest overall increase in tumor volume.
Various studies demonstrated varied correlation to disease prognosis depending on tumor cell localization and cancer type, comparing clinicopathological characteristics of ER receptor. Alpha receptors predominated in tissue types that were associated with reproduction, such as the mammary glands, uterus, vagina, and endometrium. On the contrary, ERβ is significantly expressed in tissues recognized as targets for estrogen – like in prostate and colon epithelium. Here, as shown in [Table 2], the expression of receptor in various SCC associated with PFS is formulated with recent relevant articles presented as per our search in PubMed. So as in breast carcinoma, ERα may have good prognosis or an unclear role while ERβ too demonstrated an unclear role in prognosis and ERγ role still needs to be investigated.,,, In endometrial carcinoma, decreased ERα denoted poor prognosis while increased expression of ERβ and ERγ predicted a poor survival., In uterine carcinoma, increased expression of ERα predicted poor survival. In case of colon carcinoma, increased expression of ERα showed unclear prediction while increased expression of ERβ predicted good prognosis., Vaginal carcinoma showed decreased expression of ERα associated with poor survival. In prostate carcinoma, increased expression of ERα predicted poor prognosis and increased expression of ERβ role was unclear.
|Table 2: Role of estrogen receptor α, β, and γ in the prognosis of various squamous cell carcinoma was formulated as per our search in PubMed website|
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| Conclusion|| |
As per the review, with first reported in OSCC since 1981 till 2018, various scientists have proved the expression of ERα and β expression in OSCC. Few possible explanations for survival and prognosis like aromatase activity, FAK expression, SRC-1, SERM, miR-125a, ESRRA expression by siRNA till complementary chemopreventives role 2-ME, (TOC) and 4-HPR have been suggested and studied. When TOC + 4-HPR+2-ME treatment was administered, the final result was the minimum overall increase in tumor volume.
Various studies till date propose that E2 promotes principally immunosuppressive and tumor-promoting TME (tumor microenvironment) in numerous tumors. Although checkpoint blockade immunotherapies demonstrated remarkable clinical success for the management of particular cancers, the treatment shows fractional response rates. The acquired resistance to available treatment and cancer therapies calls for the development of strategy to enhance immunotherapeutic responses. The data reviewed in [Table 3] suggests the possible mechanism of E2 pathway that controls the tumor immune reaction. Combinations of estrogen blocking agents along with immune checkpoint inhibitors may prove a vital role in clinical therapies for cancer.
|Table 3: Estrogen receptor and aromatase expression in stromal and immune cells in the tumor microenvironment|
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However, more research is warranted to prove the expression of ERα and β in prognostic way which may provide new dependable therapeutic targets for the management of OSCC and also explain a possible role of estrogen in OSCC. More research is warranted for a possible explanation of increased female predilection for OSCC in menopausal age.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]