INVESTIGATION OF THE RELATIONSHIP OF TNFRSF11A
GENE POLYMORPHISMS WITH BREAST CANCER
DEVELOPMENT AND METASTASIS RISK IN PATIENTS
WITH BRCA1 OR BRCA2 PATHOGENIC VARIANTS
LIVING IN THE TRAKYA REGION OF TURKEY
Özdemir K, Gürkan H, Demir S, Atli E, Özen Y, Sezer A, Tunçbilek N, Çicin İ
*Corresponding Author: Hakan Gürkan, MD, PhD, Department of Medical Genetics, Genetic Diseases
Diagnosis Center, Trakya University Faculty of Medicine, Balkan Campus, 22030 Edirne, Turkey. Tel:
+90-533-218-8005. Fax: +90-284-235-7641. Email: dr_hakangurkan@yahoo.de, hgurkan@trakya.edu.tr
page: 49
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INTRODUCTION
Although some progress has been made in understanding
the role of the high-risk breast cancer susceptibility
genes BRCA1 and BRCA2, what exactly has caused the
variation of risk observed among mutation carriers remains
unclear [1]. The risk of developing breast cancer varies
widely among pathogenic variation carriers of BRCA1 or
BRCA2. This apparent variability in cancer risk between
BRCA1 and BRCA2 pathogenic variation carrier families
and among individuals within families can be explained by
modifying genes that partially affect mutation penetration
[2]. In the microarray studies of irradiated lymphoblastoid
cell lines from pathogenic variation carriers of BRCA1 or
BRCA2, new genes have been found that affect and alter
the expression of certain other genes. Such genes are called
modifying genes. These modifying genes modulate penetrance,
dominance, pleiotropy, or expression in individuals
with Mendelian features [3]. Again, in some studies,
it has been observed that genotype-phenotype correlations
do not comply with intra-individual risk variations
within mutation carrier families. Accordingly, if there is no
significant correlation between mutant BRCA alleles and
phenotypes, it has been suggested that the risk of cancer
can be modulated with other genetic and environmental
factors [4]. Extensive international cohort studies show that these genes can increase the risk of breast cancer
[2]. In the literature, many different regulatory loci have
been proposed, including the nuclear receptor coactivator
3 (NCOA3, AIB1) involved in hormone metabolism, the
androgen receptor (AR) gene and the RAD51 gene involved
in DNA repair [5-7].
TNFRSF11A is a member of the tumor necrosis factor
(TNF) receptor superfamily, which includes 32 members.
The extracellular part of TNFRSF11A is a signal
peptide that consists of 28 amino acids, with a total of
616 amino acids in the transmembrane protein and 21
amino acids in the short transmembrane and large cytoplasmic
portions. The TNFRSF11A gene is localized in
chromosome 18q21.33 and has 12 exons in total [8]. It
has been determined that this receptor, which controls
osteoclastogenesis and calcium metabolism, is expressed
on the surface of macrophage/monocytic cells, T and B
lymphocytes, fibroblasts, dendritic cells, chondrocytes,
trophoblasts and precursor-mature osteoclasts [9]. The
protein synthesis of TNFRSF11A has also been shown in
some cancer cells, including those of breast and prostate
cancer, with both being types of cancer with high potential
for bone metastasis. TNFRSF11A is the only receptor that
can maintain the binding TNF superfamily member 11
receptor activator of nuclear factor κ B ligand (RANKL)
to preosteoclasts [10].
The RANKL gene encodes one of the members of
the TNF ligand family that has 18 members and it is the
key mediator of bone resorption. The encoded protein
is a 317-amino acid peptide composed of two cellular
and biologically active soluble forms that are membrane
bound [11]. It has been demonstrated with messenger RNA
(mRNA) studies that RANKL gene expression can occur
in tissues of the lymph nodes, thymus, lung, spleen, brain,
heart, intestine, kidney, liver, skeletal muscle, placenta,
testicle, skin, breast, bone marrow, active T-lymphocytes
and osteoblasts [12]. TNFRSF11A does not have the ability
to activate protein kinases spontaneously like other
TNF receptors. Therefore, after binding of RANKL, TNF
receptor-related factors can bind to the cytoplasmic part of
TNFRSF11A and activate intracellular signaling pathways.
RANKL has crucial effects on the immune system as well as
an osteoporotic effects [13]. Furthermore, preclinical studies
in mice have shown that RANKL is also expressed in
breast epithelial cells during pregnancy, and it is essential
in mammary gland development, lactational hyperplasia
of breast epithelial cells and milk production [14,15]. The
expression of some malignant tumor cells in TNFRSF11A
as well as RANKL, has suggested that they may play a role
in the stimulation of tumor cell proliferation [16].
TNFRSF11A signals can become active in progenitor
cells from core cells believed to be in BRCA1 or BRCA2
mutation carriers with breast cancer [17]. Intracellular
signaling mediated by TNFRSF11A forms the basis of
mammary gland development and regulates stem and progenitor
cell divisions. Overexpression of TNFRSF11A promotes
the abnormal proliferation of breast epithelial cells
and prevents differentiation, which increases the incidence
of tumorigenesis. As a result, dysfunctional mammary
glands that have lobuloalveolar structures can be observed.
In line with the underlying breast processes, the increased
signals of TNFRSF11A promote breast cancer formation
[8,18].
In their study, Sigl et al. [17] have reported that
TNFRSF11A signaling can play an exclusive role in
breast carcinogenesis guided by BRCA1 or BRCA2 mutations.
In order to prove the accuracy of this hypothesis,
they suggested two important conclusions by conducting
a versatile analysis of the RANKL/TNFRSF11A system
in a clinical setting. First, TNFRSF11A and RANKL are
highly expressed only by breast cancer cells with BRCA1
or BRCA2 mutations, and TNFRSF11A protein levels show
a significant correlation with tumor grade in this scenario.
Second, common TNFRSF11A polymorphisms that increase
TNFRSF11A expression levels are associated with
an increased risk of developing breast cancer in women
with the BRCA1 or BRCA2 mutations. Therefore, it has
been suggested that TNFRSF11A has a role in the aetiology
of breast cancer caused by the BRCA1 or BRCA2
mutation [17]. In our study, we examined the effects of
rs4485469, rs9646629, rs34739845, rs17069904, rs884205
and rs4941129 single nucleotide polymorphisms (SNPs) in
the TNFRSF11A gene in terms of the risk of breast cancer
development.
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