Sage Journals: Discover world-class research

Abstract

Human chorionic gonadotropin (hCG) is a peptide hormone which plays an important role during pregnancy. But its impact is not limited to pregnancy; it also influences tumor formation and metastatic outgrowth, especially in endometrial adenocarcinoma and breast cancer. This review summarizes what has been written in the literature about the role of hCG as a tumor marker in these 2 gynecological malignancies and also about the signal transduction pathways in which hCG is involved. HCG can, on the one hand, be a marker for the progression of a malignant disease, and on the other hand, it may be a point for therapeutical intervention, so further research into this molecule would be very much worthwhile.

Keywords

Breast cancer Endometrial adenocarcinoma hCG Therapy Tumor marker

Introduction

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) is a peptide hormone composed of 2 noncovalently linked subunits (α and β), which are products of different genes (1). The smaller α-subunit is composed of 95 amino acids and is also a part of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while the larger β-subunit, consisting of 145 amino acids, is specific for hCG. It is normally produced during pregnancy. LH and hCG bind to a common transmembrane receptor, which is a member of a G-protein-coupled receptor family. The receptor is composed of 11 exons and 10 introns, with a coding region of 60 kb (2).

HCG amounts in blood of men and nonpregnant women are normally around 5 IU/L, with levels increasing to 10 IU/L during climacterium (3). During the first weeks of pregnancy, blood concentrations rise even more, peaking during 10^th to 12^th week of gestation and coming back to normal values a few days after delivery (4, 5). Urinary concentrations of hCG are generally lower than those measured from blood, and determination of hCG levels is the basis of pregnancy tests. A few days after insemination the hyperglycosylated β-hCG, which is a completely independent molecule playing a role in abnormal cell growth, invasion and malignancy (6), starts to prepare the uterus for nidation of the egg and stimulates the production of progesterone, thereby inhibiting further ovulation. Secretion of hCG also induces differentiation of the mammary gland by binding specific receptors on mammary epithelial cells (7). Furthermore, hCG is used as a tumor marker in breast, lung, liver, colon and kidney tumors, but it is not a diagnostic marker, as its concentrations are too low. Therefore it is used in monitoring disease progression (8).

Endometrial adenocarcinoma

As 11,300 women in Germany are newly diagnosed with endometrial adenocarcinoma every year, it is the fourth most frequent gynecological malignancy there. However, it is difficult to diagnose endometrial adenocarcinoma, because a histological examination of tissue extracted by hysteroscopy is necessary (9). Risk factors for this malignancy are estrogen-based hormonal treatment (10), diabetes mellitus, nulliparity and former carcinomas (11). Other risk factors for the development of an endometrial adenocarcinoma could also be high body mass index (BMI) and etiology of infertility (12). In most cases, a surgical intervention is made, followed by radiotherapy, while a decision for chemotherapeutical treatment is only seldom made (13). About 25% of all patients show up with metastases, so rigorous follow-up care is indispensable (14).

Breast cancer

Breast cancer is the most often diagnosed tumor in women and the main cause of cancer-related death. In Germany about 70,000 newly diagnosed breast cancer cases are registered every year (15). In most cases, breast cancer development is due to sporadic genetic events, which lead to an activation of oncogenes and/or inactivation of tumor suppressor genes. Only in 5% of cases, can a hereditary component be detected; most of these are mutations in the BRCA genes (16 -18). Other risk factors for breast cancer development are nulliparity, early menarche, late menopause and late age at pregnancy. Thereby, the age of the first full-term pregnancy seems to play a role as a risk factor, by increasing levels of hCG, which is thought to have a protective effect on breast cells by increasing differentiation (19). Early age of full-term pregnancy has a protective effect against breast cancer (20). Nowadays, diagnosis and screening techniques are rather sophisticated (21), so that most breast cancer cases can be detected in an early stage, when therapy is still effective, thereby increasing disease-free and overall survival (22 -25). Treatment is mostly done by surgery, radiotherapy and chemotherapy, depending on tumor stage and differentiation. Thus 5-year survival rates of 80% are achieved (15).

Role of hCG in endometrial adenocarcinoma

HCG as a tumor marker

HCG was described as a tumor marker as early as 1982, when a collective of 456 different cancers was analyzed using the immunoperoxidase technique. Among these cases, 18.9% of endometrial adenocarcinomas were positive for hCG, and it was found that poorly differentiated and/or invasive tumors had the highest expression levels of hCG (26, 27). Shortly after these studies, the occurrence of hCG and carcinoembryonic antigen (CEA) were immunohistologically studied in cervical and endometrial adenocarcinomas and were regarded as useful markers in the characterization of adenocarcinomas of the uterus (28). The appearance of this marker in the blood of patients with gynecological tumors could also be helpful in evaluating the therapy response or might indicate the development of recurrence or remote metastasis (29). At the same time, it was found that the free β-subunit of hCG, asialo-free β-subunit and its core glycopeptide, referred to as urinary gonadotropin fragments (UGFs), could be detected in the urine of cancer patients, especially of endometrial adenocarcinoma patients, and that the detection of UGFs also gives some hints regarding the stage of disease (1).

A case report from 1991 confirmed these data, reporting some poorly differentiated endometrial adenocarcinomas with high hCG β-subunit levels in blood, which in fact dropped after treatment, but nevertheless the patients suffered a rapid progression and recurrence and died soon afterwards (30). Similar data were reported in 1993, where hCG levels of 2 placental tumors were compared, and the patient with the lower levels died earlier than the patient with the high levels, so it was suggested that hCG could not be regarded as a general and unique tumor marker (31, 32).

HCG is known to bind the LH receptor, so an analysis of LH receptor expression was an obvious approach. Northern and Western blotting demonstrated that the level of LH receptor proteins in patients with endometrial adenocarcinomas is much higher than in those with normal endometrium, and the level even increases with increasing tumor grade, highlighting the importance of this receptor in endometrial tumorigenesis (33 -35). In 1995, it was shown that the free β-subunit of hCG especially can be used as a tumor marker, while the significance of the α-subunit is of minor importance (36). Two further case reports from 1998 again demonstrated the importance of β-hCG as a tumor marker, connected with aggressive disease, metastasis formation and poor patient survival (37 -39). In 2004 another case of endometrial adenocarcinoma was reported, which even only produced free β-subunit of hCG, thereby producing contradictory results between serum and urine analyses (6, 40). Endometrial adenocarcinomas with low serum hCG levels, in contrast, were shown to have a better prognosis (41 -43). The finding that LH/hCG are expressed in primary endometrial adenocarcinomas and that this expression correlates with cell invasiveness led to the conclusion that recurrent and metastatic endometrial adenocarcinomas expressing these molecules could benefit from therapies lowering the LH/hCG levels with gonadotropin-releasing hormone (GnRH) analogues. Thus LH/hCG can be regarded as a prognostic factor and also a therapeutic target (44). Furthermore, also in patients with low risk of endometrial adenocarcinoma, the expression levels of LH/hCG, analyzed together with other clinicopathological factors, can help to predict recurrence risk in low-risk endometrial adenocarcinoma patients (45).

Tumorigenesis mechanism of tumorigenesis involving hCG

The mechanisms by which hCG influences cellular reactions are difficult to understand. In 1999 it was found that the mitogen-activates protein kinase (MAPK) pathway could be regulated by platelet-activating factor (PAF) and hCG in the endometrial adenocarcinoma cell line Hec-1B. The cells were therefore pretreated with medroxyprogesterone acetate and estradiol. PAF and hCG then activates the MAPK pathway, which in turn activates the cyclooxygenase 2 (COX-2) expression, but protein kinase A is still upstream of this signaling pathway (46). It was confirmed that the expression of the LH-/hCG receptor correlated with cell invasiveness (47) and was a mediator of hCG action (48).

The high expression levels of LH receptor and their obvious correlation with tumor grading led to an analysis in the endometrial adenocarcinoma cell line Hec-1A. Scientists recognized that the binding of LH/hCG to the respective receptor leads to an activation of cAMP kinase (PKA) and further downstream activations of β-1-integrin receptors and matrix metalloproteinase-2 (MMP2) secretion. These mechanisms could also be shown in primary endometrial carcinomas where they produced an increase in cell invasiveness, as demonstrated in Matrigel assays. The conclusion of this analysis was that an inhibition of LH secretion by GnRH analogues could be a new treatment option for endometrial adenocarcinomas (49, 50). Furthermore, it does not seem to make a difference for LH receptor activation if hCG, hCG β-subunit or the hyperglycosylated form of hCG β-subunit bind to this receptor (51).

In contrast to these results were those of a study from 2007, in which the LH receptor and its response to hCG was analyzed in the Ishikawa cell line. Although the LH receptor was confirmed to be present as a full-length molecule, it could not be activated by hCG for downstream signaling. It was thus presumed that the Ishikawa cells used a pathway different from the conventional LH/hCG receptor signaling pathway (52).

A recent study by the group of Chen et al demonstrated that hCG induced the overexpression of β1,4galactosyltransferase I (β1,4GalT I) in RL95 cells. β1,4GalT I in turn regulates the expression of molecules such as TIMP-1, LN and MMPs, which alter cell adhesive properties. It was furthermore demonstrated that hCG also increased epidermal growth factor receptor (EGFR) signaling, a process which normally plays a role in embryo implantation, a process which, further, is rather similar to tumor invasion (53). From these results it could be concluded that hCG has different tasks within the female body, which have not yet been fully clarified.

Role of hCG in breast cancer

HCG as a tumor marker

The fact that hCG might serve as a tumor marker in breast cancer was already recognized at the beginning of the 1970s (54, 55). Also the prognostic relevance of hCG (in particular, that of the α-subunit of hCG was shown early) in the correlation of the occurrence of this subunit with lymph node metastases and a poorer prognosis for patient survival was depicted (56). In the following years, the importance given to hCG as a breast cancer marker decreased a lot (57, 58), although it could be demonstrated that malignant breast cancer cells produce hCG, as confirmed by the intracellular location of the molecule (59). In the beginning of the 1980s, there was doubt regarding the usefulness of hCG as a serum marker in metastatic breast cancer and its significance in monitoring palliative treatment, as other markers such as alkaline phosphatase (AP), CEA and tissue polypeptide antigen (TPA) had higher rates of occurrence and could be related to other tumor characteristics (60). For hCG, no clinical relevance could be seen (61 -64), especially as it was found to also be expressed in healthy breast tissue (65). But scientists in this period agreed that hCG was expressed to a higher degree in postmenopausal women (63, 66).

A study from 1988 finally recognized hCG as a tumor marker for breast cancer again (67). Almost 10 years later, the role of hCG in breast cell differentiation was clarified, and its inhibitory role in mammary carcinogenesis was presumed (68). A few years later, a correlation between hCG and progesterone receptor was found, suggesting a regulation of hCG expression by progestins, but no correlation between hCG expression and disease-free and overall survival was seen (69). A multimarker reverse transcriptase polymerase chain reaction (RT-PCR) assay could then demonstrate a correlation of hCG and a tumor-associated antigen (MAGE-A3) with tumor size (70).

In general, hCG was described as a useful real-time PCR marker (71) for the detection of circulating tumor cells – for example, in combination with mammaglobin (hMAM) (72) or cytokeratin 19 (73). The RT-PCR technique with CK19, CK20 and hCG as marker genes was also used to demonstrate that fine-needle aspiration of breast tissue might introduce cancer cells in the blood stream (74). Again a few years later a coherence between the messenger RNA (mRNA) presence of hCG β-subunit genes 3, 5 and 8 and relapse-free survival could be shown by molecular beacon reverse transcriptase PCR (75). HCG could furthermore be correlated to inhibin expression, and a high expression of hCG was measured in apocrine tumor types, so that it could help to characterize tumors (76).

A prediction of metastatic outgrowth and therapy response and monitoring was promoted by the group of Francia et al in 2008 (77). Furthermore, it was shown that there was no difference in the significance of total hCG and free β-subunit of hCG, as both could be related to maternal breast cancer risk (78). Recently it could even be demonstrated that hCG promotes normal breast cell differentiation in animal models, and administration of hCG or generally higher hCG levels prevent occurrence of breast cancer development in mice, but no inverse correlation between pregnancy and reduced breast cancer risk was shown (79).

Tumorigenesis mechanism of tumorigenesis involving hCG

In 1994, scientists began to clarify the mechanisms of the functioning of hCG. In hCG-treated human breast cancer cell lines, some mRNAs and proteins were produced to a higher extent, while others were down-regulated in comparison with untreated control cells, but the assignment of these mRNAs and proteins respectively could not be clarified yet (80). In the experiments that followed, a higher expression of p53, c-myc and ICE could be described in hCG-treated cells, so that hCG seemed to exert an apoptotic influence on breast cancer cells (81 -84). It could again be shown, that the growth inhibitory effect of hCG on breast cancer cells was dependent on the presence of the LH/hCG receptor (85). Also the expression of inhibin was found to be elevated after hCG treatment, leading to mammary gland differentiation and tumor regression (86). Thus inhibin and hCG effectuates an increase in histone acetylation (87). In contrast to that, hCG was found to stimulate the growth of tumor cells in the presence of estrogen and estrogen response elements (ERE) by increasing ERE-mediated transcription. Therefore GnRH analogues could be effective therapeutic agents in women suffering from postmenopausal breast cancer (88, 89).

Furthermore, hCG seems to influence the expression of Hox genes, depending on the splice variant of the LH receptor that is present in the respective cell type (87). Not only genes for apoptosis and inhibition of cell proliferation but also genes regulating DNA repair and the impaired binding of carcinogens to the DNA are highly expressed due to the action of hCG (90). Furthermore, hCG not only leads to a reduction of cell proliferation but obviously also to a decrease in cell invasion. These 2 effects are provoked by a down-regulation of NF-kB and AP-1 via a cAMP-dependent protein kinase signaling pathway driven by hCG (91).

In contrast to the protective effects that hCG has in most breast cancer cases, in pregnancy-associated breast cancer, hCG seems to play a different role: in this special type of breast cancer, which occurs during pregnancy or within 1 year after delivery, it seems to increase neovascularization via vascular endothelial growth factor (VEGF), a process which is crucial to metastatic outgrowth (92). Another reason for these pregnancy-induced tumors could be an up-regulation of certain molecules from the Wnt-signaling pathway – for example, Wnt 5b and 7b (93).

Returning to the subject of the cancer-protective effects, which are the major modes of action of hCG, it was recognized that cancer protection is mediated by α-fetoprotein (AFP), in the process through which hCG elicits AFP from the nonpregnant liver (94). The high levels of hCG found in patients suffering from choriocarcinoma were also reported to be protective against breast cancer (95). The ambivalent function of hCG as a breast cancer promoting or protecting agent is also seen in invasive vs. noninvasive breast cancer: In invasive tumors of the breast, an up-regulation of the LH/hCG receptor was found, indicating that hormones which target these receptors could favor the generation of mammary tumors (96). There is evidence, for example, that there are a low number of LH/hCG receptors on breast cancer cells, which suggest a more indirect way of signaling effects, and that these signaling effects may occur through the ovaries (20).

Whether hCG favors or impairs tumor formation is obviously dependent on the receptors, which are found at the surface of breast epithelial cells. This was demonstrated by Iezzi et al, who used a mouse model for their analyses and found that tumor progression via hCG occurs, if mammary cells are positive for the expression of LH/hCG or ERBB-2 receptor (97). Additionally, there are indirect endocrine effects of the cells, which influence cancer outgrowth (98). As already presumed in 2002, hCG influences histone modification, in turn affecting chromatin condensation levels and thereby regulating gene expression. The occurrence of hCG was correlated to the presence of me2H3K9 and me3H3K27, which are known markers for heterochromatin or facultative heterochromatin, respectively. Thus the genomic structure of breast cell differentiation is kept up, and carcinogenesis is prevented (99). In conclusion it can be said that in most cases hCG has a protective effect on breast cancer formation by reducing cell proliferation and increasing differentiation (100, 101).

HCG in breast cancer therapy

It was recognized early that a large number of patients with metastatic breast cancer had high hCG levels in their serum, and that levels corresponded to responses to combination chemotherapy, so hCG could be considered as a therapeutic marker (102). But hCG administration also seemed to reduce breast cancer risk, especially in women with nonobese BMI (103). Additionally, hCG also contributes to a higher radiosensitivity of breast cancer cells, at least in a cell culture model using MCF7 cells (in concentration of 2 IU/mL hCG at 24 hours before irradiation with 4 Gy for MCF7 cells) (7).

Another interesting approach was to use hCG as a DNA vaccine for active-specific immunotherapy in controlling mammary tumor progression. Thus BALB/c mice were vaccinated with a plasmid carrying 6 copies of a part of the hCG DNA sequence. Vaccinated animals had higher antibody avidity and improved immunogenicity, thus this would seem to be another promising approach for combating breast cancer via hCG (104).

As hCG also might increase rates of apoptotic cell death, it could be used preceding local or systemic therapy to improve therapy response. This presumption was confirmed by xenograft analysis and seems to be a promising approach (105).

In 2007, another interesting study with respect to hCG in cancer therapy was performed. Women with newly diagnosed breast cancer received recombinant hCG (rhCG) 2 weeks before surgery. After surgery, tumor tissue was analyzed, and a reduction of the proliferative index and expression of estrogen and progesterone receptors were found in comparison with the control group who only received placebo. Also in metastatic breast cancer, rhCG had beneficial effects, so that further studies on this topic would be worthwhile (106).

Also, a long-term protective effect of pregnancy hCG of breast cancer has been described in the literature, depending on age at pregnancy and breast cancer diagnosis (107, 108). A study from 2011 even postulated that hCG prevents the formation of cancer stem cells via down-regulation of CXCR-1 expression, thereby preventing further cancer outgrowth and metastasis formation (109). An infertility treatment with hCG was also presumed to have breast cancer–protective effects (110).

Further interesting facts regarding hCG and its correlation with breast cancer

LH/hCG seems to play a role not only in female but also in male breast cancer, as shown in the fact that LH/hCG receptors were found during an autopsy of male breast cancer patients. But the function of these receptors in the male form of breast cancer still has to be clarified (111).

Pregnancies from which children with Down syndrome are born are characterized by high hCG levels in the first and up to the middle of the second trimester. A large study from Norway and Sweden analyzed the effects of these high hCG levels on breast cancer risk for mothers who gave birth to Down syndrome children, and found that risk for breast cancer development increased by 23%, especially if mothers were delivering at age >30 years (112).

Although the expression of hCGβ has been described already in many nontrophoblastic tumors, up to now there is only 1 case reported in the literature in which hCG was also found to be expressed in a phyllodes tumor, especially in the epithelioid stroma of the tumor (113).

Conclusions

HCG is a glycoprotein, which occurs physiologically in women and even in men, but it is up-regulated during pregnancy, playing a role in nidation and nutrition of the early embryo. If the occurrence of this molecule within the body is increased without pregnancy it can stimulate tumor outgrowth. Both in endometrial adenocarcinoma and in breast cancer, hCG seems to be an important tumor marker, not only for tumor cell detection, but also for characterization. The signal transduction pathways by which hCG acts in these 2 gynecological malignancies are not yet clarified completely, but further research would be worthwhile, as hCG seems to offer possibilities for tumor treatment.

Footnotes

Disclosures

Financial support: No grants or funding have been received for this study.

Conflict of interest: None of the authors has any financial interest related to this study to disclose.

References

Cole

Wang

Elliott

et al . Urinary human chorionic gonadotropin free beta-subunit and beta-core fragment: a new marker of gynecological cancers. Cancer Res. 1988;48(5): 1356-1360.

Jiang

Russo

. Alternately spliced luteinizing hormone/human chorionic gonadotropin receptor mRNA in human breast epithelial cells. Int J Oncol. 2002;20(4):735-738.

Thomas

. Labor und Diagnose. 5th ed. 2000.

Cacciatore

Stenman

Ylöstalo

. Diagnosis of ectopic pregnancy by vaginal ultrasonography in combination with a discriminatory serum hCG level of 1000 IU/l (IRP). Br J Obstet Gynaecol. 1990;97(10):904-908.

Cacciatore

Tiitinen

Stenman

Ylöstalo

. Normal early pregnancy: serum hCG levels and vaginal ultrasonography findings. Br J Obstet Gynaecol. 1990;97(10):899-903.

Muller

Cole

. The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol. 2009;112(3):663-672.

Pond-Tor

Rhodes

Dahlberg

Leith

McMichael

Dahlberg

. Enhancement of radiosensitivity of the MCF-7 breast cancer cell line with human chorionic gonadotropin. Breast Cancer Res Treat. 2002;72(1):45-51.

Sjöström

Alfthan

Joensuu

Stenman

Lundin

Blomqvist

. Serum tumour markers CA 153, TPA, TPS, hCGbeta and TATI in the monitoring of chemotherapy response in metastatic breast cancer. Scand J Clin Lab Invest. 2001;61(6):431-441.

Marsden

Hacker

. Optimal management of endometrial hyperplasia. Best Pract Res Clin Obstet Gynaecol. 2001;15(3):393-405.

10.

Emons

Heyl

. Hormonal treatment of endometrial cancer. J Cancer Res Clin Oncol. 2000;126(11):619-623.

11.

Hecht

Mutter

. Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol. 2006;24(29):4783-4791.

12.

Karimi Zarchi

Rouhi

Abdolahi

Hekmatimoghaddam

. The effect of assisted reproductive technologies on gynecological cancer: report of our experiences and literature review. Int J Biomed Sci. 2013;9(3):129-134.

13.

Amant

Moerman

Neven

Timmerman

Van Limbergen

Vergote

. Treatment modalities in endometrial cancer. Curr Opin Oncol. 2007;19(5):479-485.

14.

Beckmann

Iosifidis

Shorne

Gilchrist

Roder

. Effects of variations in hysterectomy status on population coverage by cervical screening. Aust N Z J Public Health. 2003;27(5):507-512.

15.

e.V., R. K. I. u. d. G. d. e. K. i. D. Krebs in Deutschland 2011/2012. 10th ed. 2015.

16.

Antoniou

Pharoah

Narod

et al . Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.

17.

Frank

Deffenbaugh

Reid

et al . Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20(6): 1480-1490.

18.

Levy-Lahad

Friedman

. Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2007;96(1):11-15.

19.

Gehring

Siepmann

Heidegger

Jeschke

. The controversial role of human chorionic gonadotropin in the development of breast cancer and other types of tumors. Breast. 2016;26:135-140.

20.

Kuijper

Ruigrok-Ritstier

Verhoef-Post

et al . LH receptor gene expression is essentially absent in breast tumor tissue: implications for treatment. Mol Cell Endocrinol. 2009;302(1):58-64.

21.

Smith

Duffy

Tabar

. Breast cancer screening: the evolving evidence. Oncology (Williston Park). 2012;26(5): 471-475, 479-481, 485-486.

22.

Cianfrocca

Goldstein

. Prognostic and predictive factors in early-stage breast cancer. Oncologist. 2004;9(6):606-616.

23.

Elkin

Hudis

Begg

Schrag

. The effect of changes in tumor size on breast carcinoma survival in the U.S.: 19751999. Cancer. 2005;104(6):1149-1157.

24.

Narod

. Tumour size predicts long-term survival among women with lymph node-positive breast cancer. Curr Oncol. 2012;19(5):249-253.

25.

Rosen

Groshen

Kinne

Norton

. Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol. 1993;11(11):2090-2100.

26.

Fenoglio

Crum

Ferenczy

. Endometrial hyperplasia and carcinoma: are ultrastructural, biochemical and immunocytochemical studies useful in distinguishing between them? Pathol Res Pract. 1982;174(3):257-284.

27.

Fenoglio

Hayata

Crum

Richart

. The expression of human chorionic gonadotropin in the female genital tract: localization by the immunoperoxidase technique. Diagn Gynecol Obstet. 1982;4(2):97-103.

28.

Ueda

Yamasaki

Inoue

et al . Immunohistological study of isoantigens, carcinoembryonic antigen and human chorionic gonadotropin in adenocarcinomas of the uterus. Nihon Sanka Fujinka Gakkai Zasshi. 1984;36(3):437-442.

29.

Restaino

Traina

Putignano

et al . Valuation of some markers in the malignant neoplastic pathology of the female genital tract. Eur J Gynaecol Oncol. 1988;9(1):30-32.

30.

Pesce

Merino

Chambers

Nogales

. Endometrial carcinoma with trophoblastic differentiation: an aggressive form of uterine cancer. Cancer. 1991;68(8):1799-1802.

31.

Chatzaki

Gallagher

Iles

et al . Characterisation of the differential expression of marker antigens by normal and malignant endometrial epithelium. Br J Cancer. 1994;69(6):1010-1014.

32.

Fukunaga

Ushigome

. Metastasizing placental site trophoblastic tumor: an immunohistochemical and flow cytometric study of two cases. Am J Surg Pathol. 1993;17(10):1003-1010.

33.

Chen

Aoyoma

Liu

. Increased expression of human luteinizing hormone/human chorionic gonadotropin receptor mRNA in human endometrial cancer. Mol Cell Probes. 2002; 16(4):269-275.

34.

Konishi

Koshiyama

Mandai

et al . Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women. Gynecol Oncol. 1997;65(2): 273-280.

35.

Lin

Lei

Lojun

Rao

Satyaswaroop

Day

. Increased expression of luteinizing hormone/human chorionic gonadotropin receptor gene in human endometrial carcinomas. J Clin Endocrinol Metab. 1994;79(5):1483-1491.

36.

Grossmann

Hoermann

Gocze

Ott

Berger

Mann

. Measurement of human chorionic gonadotropin-related immunoreactivity in serum, ascites and tumour cysts of patients with gynaecologic malignancies. Eur J Clin Invest. 1995;25(11):867-873.

37.

Bradley

Benjamin

Wheeler

Rubin

. Endometrial adenocarcinoma with trophoblastic differentiation. Gynecol Oncol. 1998;69(1):74-77.

38.

Ishi

Suzuki

Saito

Koyatsu

Akutsu

Kubota

. Cytodiagnosis of placental site trophoblastic tumor. a report of two cases. Acta Cytol. 1998;42(3):745-750.

39.

Lee

Pattillo

Bouzyk

Oprea-Ilies

Matthews

. Endometrial carcinoma with ectopic human chorionic gonadotropin expression. Gynecol Oncol Rep. 2015;12:45-8.

40.

Grenache

Moller

Groben

. Endometrial adenocarcinoma associated with elevated serum concentrations of the free beta subunit of human chorionic gonadotropin. Am J Clin Pathol. 2004;121(5):748-753.

41.

Akbulut

Tosun

Soysal

Oztekin

. Endometrioid carcinoma of the endometrium with choriocarcinomatous differentiation: a case report and review of the literature. Arch Gynecol Obstet. 2008;278(1):79-84.

42.

Carta

Accurti

Di Nicola

et al . Uterine endometrioid carcinoma with focal area of choriocarcinomatous differentiation: case report. Eur J Gynaecol Oncol. 2014;35(6):731-733.

43.

Horn

Hanel

Bartholdt

Dietel

. Serous carcinoma of the endometrium with choriocarcinomatous differentiation: a case report and review of the literature indicate the existence of 2 prognostically relevant tumor types. Int J Gynecol Pathol. 2006;25(3):247-251.

44.

Arcangeli

Noci

Fortunato

Scarselli

. The LH/hCG axis in endometrial cancer: a new target in the treatment of recurrent or metastatic disease. Obstet Gynecol Int. 2010;2010.

45.

Noci

Sorbi

Mannini

et al . LH/hCG-receptor expression may have a negative prognostic value in low-risk endometrial cancer. Front Oncol. 2016;6:190.

46.

Munir

Fukunaga

Miyazaki

Okamura

Miyamoto

. Mitogen-activated protein kinase activation and regulation of cyclooxygenase 2 expression by platelet-activating factor and hCG in human endometrial adenocarcinoma cell line HEC-1B. J Reprod Fertil. 1999;117(1):49-59.

47.

Noci

Pillozzi

Lastraioli

et al . hLH/hCG-receptor expression correlates with in vitro invasiveness in human primary endometrial cancer. Gynecol Oncol. 2008;111(3):496-501.

48.

Jankowska

Andrusiewicz

Grabowski

Nowak-Markwitz

Warchol

. Coexpression of human chorionic gonadotropin beta subunit and its receptor in nontrophoblastic gynecological cancer. Int J Gynecol Cancer. 2008;18(5):1102-1107.

49.

Dabizzi

Noci

Borri

et al . Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. Cancer Res. 2003;63(14):4281-4286.

50.

Jankowska

Andrusiewicz

Fischer

Warchol

. Expression of hCG and GnRHs and their receptors in endometrial carcinoma and hyperplasia. Int J Gynecol Cancer. 2010;20(1):92-101.

51.

Cole

Butler

. Hyperglycosylated hCG, hCGβ and hyperglycosylated hCGβ: interchangeable cancer promoters. Mol Cell Endocrinol. 2012;349(2):232-238.

52.

Viswanath

Chatterjee

Roy

. Assessment of luteinizing hormone receptor function in an endometrial cancer cell line, Ishikawa cells in response to human chorionic gonadotrophin (hCG). Mol Cell Endocrinol. 2007;272(1-2):14-21.

53.

Chen

Xie

Fan

et al . HCG induces β1,4-GalT I expression and promotes embryo implantation. Int J Clin Exp Pathol. 2015; 8(5):4673-4683.

54.

Sheth

Saruiya

Ranadive

Sheth

. Ectopic production of human chorionic gonadotrophin by human breast tumours. Br J Cancer. 1974;30(6):566-570.

55.

Tormey

Waalkes

Ahmann

et al . Biological markers in breast carcinoma: Part I: incidence of abnormalities of CEA, HCG, three polyamines, and three minor nucleosides. Cancer. 1975;35(4):1095-1100.

56.

Walker

. Significance of alpha-subunit HCG demonstrated in breast carcinomas by the immunoperoxidase technique. J Clin Pathol. 1978;31(3):245-249.

57.

Waalkes

Gehrke

Tormey

et al . Biologic markers in breast carcinoma: Part IV: serum fucose-protein ratio: comparisons with carcinoembryonic antigen and human chorionic gonadotrophin. Cancer. 1978;41(5):1871-1882.

58.

Wahren

Lidbrink

Wallgren

Eneroth

Zajicek

. Carcinoembryonic antigen and other tumor markers in tissue and serum or plasma of patients with primary mammary carcinoma. Cancer. 1978;42(4):1870-1878.

59.

Castro

Buschbaum

Nadji

Voigt

Tabei

Morales

. Immunochemical demonstration of human chorionic gonadotrophin (hCG) in tissue of breast carcinoma. Acta Endocrinol (Copenh). 1980;94(4):511-516.

60.

Caffier

Brandau

. Serum tumor markers in metastatic breast cancer and course of disease. Cancer Detect Prev. 1983;6(4-5): 451-457.

61.

Kuida

Braunstein

Shintaku

Said

. Human chorionic gonadotropin expression in lung, breast, and renal carcinomas. Arch Pathol Lab Med. 1988;112(3):282-285.

62.

Lee

Rosen

DeLellis

et al . Tumor marker expression in breast carcinomas and relationship to prognosis. An immunohistochemical study. Am J Clin Pathol. 1985;84(6):687-696.

63.

Monteiro

Ferguson

McKinna

Greening

Neville

. Ectopic production of human chorionic gonadotrophin-like material by breast cancer. Cancer. 1984;53(4):957-962.

64.

Wachner

Wittekind

von Kleist

. Immunohistological localization of beta-HCG in breast carcinomas. Eur J Cancer Clin Oncol. 1984;20(5):679-684.

65.

Loganath

Peh

Gunasegaram

et al . Comparison of AFP and beta-hCG levels in infiltrating duct mammary carcinoma at different stages of malignancy. Pathology. 1988;20(3):275-278.

66.

Borkowski

Puttaert

Gyling

Muquardt

Body

. Human chorionic gonadotropin-like substance in plasma of normal nonpregnant subjects and women with breast cancer. J Clin Endocrinol Metab. 1984;58(6):1171-1178.

67.

Kardana

Taylor

Southall

Boxer

Rowan

Bagshawe

. Urinary gonadotrophin peptideisolation and purification, and its immunohistochemical distribution in normal and neoplastic tissues. Br J Cancer. 1988;58(3):281-286.

68.

Meduri

Charnaux

Loosfelt

et al . Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer. Cancer Res. 1997;57(5):857-864.

69.

Reimer

Koczan

Müller

et al . Human chorionic gonadotrophin-beta transcripts correlate with progesterone receptor values in breast carcinomas. J Mol Endocrinol. 2000;24(1):33-41.

70.

Taback

Chan

Kuo

et al . Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease. Cancer Res. 2001;61(24):8845-8850.

71.

Hoon

Sarantou

Doi

et al . Detection of metastatic breast cancer by beta-hCG polymerase chain reaction. Int J Cancer. 1996;69(5):369-374.

72.

Fabisiewicz

Kulik

Kober

Brewczyńska

Pieńkowski

Siedlecki

. Detection of circulating breast cancer cells in peripheral blood by a two-marker reverse transcriptase-polymerase chain reaction assay. Acta Biochim Pol. 2004;51(3):747-755.

73.

Chow

. Detection of circulating breast cancer cells with multiple-marker RT-PCR assay. Anticancer Res. 2001;21(1A):421-424.

74.

Chow

. Fine needle aspiration may shed breast cells into peripheral blood as determined by RT-PCR. Oncology. 2000;59(3):217-222.

75.

Span

Manders

Heuvel

et al . Molecular beacon reverse transcription-PCR of human chorionic gonadotropin-beta-3, -5, and -8 mRNAs has prognostic value in breast cancer. Clin Chem. 2003;49(7):1074-1080.

76.

Chang

Lee

Kim

Kang

. The immunoexpressions and prognostic significance of inhibin alpha and beta human chorionic gonadotrophins (HCG) in breast carcinomas. Cancer Res Treat. 2005;37(4):241-246.

77.

Francia

Emmenegger

Lee

et al . Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using beta-human choriogonadotropin secreting tumor cell lines. Mol Cancer Ther. 2008;7(10):3452-3459.

78.

Toriola

Tolockiene

Schock

et al . Free β-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer. Future Oncol. 2014;10(3): 377-384.

79.

Fortner

Schock

Kaaks

et al . Human chorionic gonadotropin does not correlate with risk for maternal breast cancer: results from the Finnish Maternity Cohort. Cancer Res. 2017; 77(1):134-141.

80.

Russo

. Polypeptide pattern of human breast epithelial cells following human chorionic gonadotropin (hCG) treatment. Electrophoresis. 1994;15(5):746-750.

81.

Srivastava

Russo

Mgbonyebi

Russo

. Growth inhibition and activation of apoptotic gene expression by human chorionic gonadotropin in human breast epithelial cells. Anticancer Res. 1998;18(6A):4003-4010.

82.

Srivastava

Russo

. Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death. Carcinogenesis. 1997;18(9):1799-1808.

83.

Srivastava

Silva

Russo

Mgbonyebi

Russo

. Identification of new genes differentially expressed in breast carcinoma cells treated with human chorionic gonadotropin. Int J Oncol. 1998;13(3):465-469.

84.

Yuri

Kinoshita

Emoto

Yoshizawa

Tsubura

. Human chorionic gonadotropin suppresses human breast cancer cell growth directly via p53-mediated mitochondrial apoptotic pathway and indirectly via ovarian steroid secretion. Anticancer Res. 2014;34(3):1347-1354.

85.

Lojun

Bao

Lei

Rao

. Presence of functional luteinizing hormone/chorionic gonadotropin (hCG) receptors in human breast cell lines: implications supporting the premise that hCG protects women against breast cancer. Biol Reprod. 1997;57(5):1202-1210.

86.

Srivastava

Russo

. Inhibition of rat mammary tumorigenesis by human chorionic gonadotropin associated with increased expression of inhibin. Mol Carcinog. 1999;26(1): 10-19.

87.

Jiang

Russo

. Human chorionic gonadotropin and inhibin induce histone acetylation in human breast epithelial cells. Int J Oncol. 2002;20(1):77-79.

88.

Popnikolov

Yang

Liu

Guzman

Nandi

. Reconstituted normal human breast in nude mice: effect of host pregnancy environment and human chorionic gonadotropin on proliferation. J Endocrinol. 2001;168(3):487-496.

89.

Tanaka

Kuwabara

Okazaki

et al . Gonadotropins stimulate growth of MCF-7 human breast cancer cells by promoting intracellular conversion of adrenal androgens to estrogens. Oncology. 2000;59(Suppl 1):19-23.

90.

Guo

Russo

Lareef

Russo

. Effect of human chorionic gonadotropin in the gene expression profile of MCF-7 cells. Int J Oncol. 2004;24(2):399-407.

91.

Rao

ChV

Manna

Lei

Aggarwal

. Human chorionic gonadotropin decreases proliferation and invasion of breast cancer MCF-7 cells by inhibiting NF-kappaB and AP-1 activation. J Biol Chem. 2004;279(24):25503-25510.

92.

Michel

Aguilar

Arrieta

. Human chorionic gonadotropin as an angiogenic factor in breast cancer during pregnancy. Med Hypotheses. 2007;68(5):1035-1040.

93.

Kuorelahti

Rulli

Huhtaniemi

Poutanen

. Human chorionic gonadotropin (hCG) up-regulates wnt5b and wnt7b in the mammary gland, and hCGbeta transgenic female mice present with mammary Gland tumors exhibiting characteristics of the Wnt/beta-catenin pathway activation. Endocrinology. 2007;148(8):3694-3703.

94.

Jacobson

Lemanski

Narendran

Agarwal

Bennett

Andersen

. Hormones of pregnancy, alpha-feto protein, and reduction of breast cancer risk. Adv Exp Med Biol. 2008;617:477-484.

95.

Gudipudi

Hartzfeld

Montemarano

Del Priore

. Decreased breast cancer rates among women with choriocarcinoma. Gynecol Oncol. 2008;110(2):202-205.

96.

Hudelist

Wuelfing

Czerwenka

et al . Beta-LH/hCG receptor (b-LH/hCG) expression is increased in invasive versus preinvasive breast cancer: implications for breast carcinogenesis? J Cancer Res Clin Oncol. 2009;135(2):191-195.

97.

Iezzi

Quaglino

Cappello

et al . HCG hastens both the development of mammary carcinoma and the metastatization of LH/hCG and ERBB-2 receptor-positive cells in mice. Int J Immunopathol Pharmacol. 2011;24(3):621-630.

98.

Boukaidi

Cooley

Hardy

Matthews

Zelivianski

Jeruss

. Impact of infertility regimens on breast cancer cells: follicle-stimulating hormone and luteinizing hormone lack a direct effect on breast cell proliferation in vitro. Fertil Steril. 2012;97(2):440-444.

99.

Russo

. Molecular basis of pregnancy-induced breast cancer prevention. Horm Mol Biol Clin Investig. 2012;9(1):3-10.

100.

Liao

Wang

et al . Human chorionic gonadotropin decreases human breast cancer cell proliferation and promotes differentiation. IUBMB Life. 2014;66(5):352-360.

101.

Santucci-Pereira

George

Armiss

et al . Mimicking pregnancy as a strategy for breast cancer prevention. Breast Cancer Manag. 2013;2(4):283-294.

102.

Tormey

Waalkes

Simon

. Biological markers in breast carcinoma: Part II: clinical correlations with human chorionic gonadotrophin. Cancer. 1977;39(6):2391-2396.

103.

Bernstein

Hanisch

Sullivan-Halley

Ross

. Treatment with human chorionic gonadotropin and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 1995;4(5):437-440.

104.

Rong

Yankai

et al . Improved efficacy of DNA vaccination against breast cancer by boosting with the repeat beta-hCG C-terminal peptide carried by mycobacterial heat-shock protein HSP65. Vaccine. 2006;24(14):2575-2584.

105.

Lopez

Sekharam

Coppola

Carter

. Purified human chorionic gonadotropin induces apoptosis in breast cancer. Mol Cancer Ther. 2008;7(9):2837-2844.

106.

Janssens

Russo

et al . Human chorionic gonadotropin (hCG) and prevention of breast cancer. Mol Cell Endocrinol. 2007;269(1-2):93-98.

107.

Lukanova

Andersson

Wulff

et al . Human chorionic gonadotropin and alpha-fetoprotein concentrations in pregnancy and maternal risk of breast cancer: a nested case-control study. Am J Epidemiol. 2008;168(11):1284-1291.

108.

Toniolo

Grankvist

Wulff

et al . Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer. Cancer Res. 2010;70(17):6779-6786.

109.

Noronha

Correa-Noronha

Russo

de Cicco

Santucci-Pereira

Russo

. Human chorionic gonadotropin and a 15 amino acid hCG fragment of the hormone induce downregulation of the cytokine IL-8 receptor in normal breast epithelial cells. Horm Mol Biol Clin Investig. 2011;6(3):241-245.

110.

Cooley

Matthews

Zelivianski

Hardy

Jeruss

. Effect of infertility treatment and pregnancy-related hormones on breast cell proliferation in vitro. Hum Reprod. 2012;27(1):146-152.

111.

Carlson

Kane

Lei

Rao

. Presence of luteinizing hormone/human chorionic gonadotropin receptors in male breast tissues. J Clin Endocrinol Metab. 2004;89(8):4119-4123.

112.

Bjørge

Cnattingius

Engeland

Tretli

Lie

Lukanova

. Fetal Down syndrome and the risk of maternal breast cancer. Epidemiology. 2009;20(4):584-589.

113.

Reisenbichler

Krontiras

Hameed

. Beta-human chorionic gonadotropin production associated with phyllodes tumor of the breast: an unusual paraneoplastic phenomenon. Breast J. 2009;15(5):527-530.

The importance of hCG in human endometrial adenocarcinoma and breast cancer

Abstract

Keywords

Introduction

Human chorionic gonadotropin

Endometrial adenocarcinoma

Breast cancer

Role of hCG in endometrial adenocarcinoma

HCG as a tumor marker

Tumorigenesis mechanism of tumorigenesis involving hCG

Role of hCG in breast cancer

HCG as a tumor marker

Tumorigenesis mechanism of tumorigenesis involving hCG

HCG in breast cancer therapy

Further interesting facts regarding hCG and its correlation with breast cancer

Conclusions

Footnotes

Disclosures

References