Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer
Introduction
Breast cancer is the most commonly occurring malignant disease in women [1]. For decades, the traditional pathologic diagnosis in terms of histological subtype, grade, tumor size, lymph node involvement, and status of estrogen and HER-2 receptor, was thought to be the “gold standard”. However, it is known that patients with the same pathologic subtypes frequently have different outcomes. One possible reason is that breast cancer is a clinically heterogeneous disease, and traditional pathologic classification does not fully capture its various biological and clinical causes.
A significant improvement in diagnosis was achieved in the last decade by detailed molecular analysis of breast cancer which has provided new insights into the classification of the disease [2], [3]. Patients with breast cancer can be stratified into at least four major molecular subtypes: luminal A, luminal B, HER-2, and basal-like carcinoma based on the expression of biomarkers ER, HER-2, CK5/6 and EGFR by immunohistochemistry or/and gene analysis [4], [5]. With this new classification, prognostic information can be better provided than the standard assessment of clinical variables. This is because luminal-like cancers tend to have the most favorable long-term survival compared to the others [6]. Besides, luminal B tends to have a poor prognosis compared to luminal A [7], [8]. Moreover, the new classification can be used as a predicator of the benefits from adjuvant therapy: luminal-like cancers are treated with hormone therapy whereas basal-like and HER-2-positive cancers are more sensitive to chemotherapy [2].
However, accumulated evidence indicates that other biomarkers besides ER, HER-2, CK5/6 and EGFR are also needed to better predict clinical outcomes and/or adjuvant therapy regime decisions. For examples, Finetti et al. showed that there was a subset of patients with luminal A tumors, called Ab which expressed mitotic kinases, had a poorer prognosis than the majority that did not express kinases [9]. This research group also showed that Ki67, p53 and GATA3 can make better prognosticators in predicting outcomes for luminal breast cancer patients receiving hormone therapy [10]. In Cheang et al., Ki67 together with ER and HER-2 were found to be useful in distinguishing between luminal A and luminal B [11], while Ribeiro-Silva et al. demonstrated that the detection of VEGF could contribute to the basal-like subtype [12].
Moreover, since tumor immunoediting mechanisms play a critical role in cancer development, progress, metastasis and recurrence [13], it should be also very important to investigate biomarkers that are associated with the host immune response status. Previously, we had demonstrated that human leukocyte antigen G (HLA-G), a non-classical HLA class I molecule, was aberrantly expressed in breast cancer and that the expression was inversely associated with the clinical outcome [14]. Since HLA-G is functionally involved in tumor escape mechanisms [15], [16], we hypothesize in this paper that HLA-G and host immune response might also serve as improved prognosticators in predicting outcomes by using molecular subtype classification. To verify our hypothesis, the associations of HLA-G expression and host immune response were investigated in 104 breast cancer patients with various molecular subtypes. For comparison, Ki67, p53 and VEGF were also examined.
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Patients
A total of 104 patients with breast invasive ductal cancer, diagnosed and treated between 2008 and 2010 at the Sichuan Provincial People’s Hospital in Chengdu, Sichuan, PR China, were investigated in our study. The study was approved and monitored by the ethics committee at the hospital.
The mean age at the time of diagnosis was 49 years old (SD = 10.3 years). The clinicopathological findings were determined according to the classification of malignant tumors as set out by the International Union
Correlation of molecular subtypes and clinicopathological parameters
The correlation of tumor molecular subtypes and clinicopathological parameters such as menopause status, tumor histological grade, tumor vascular invasion status, tumor size, nodal status, and clinical stages are shown in Table 2. There was no significant correlation between these parameters and the subtypes.
Correlation of molecular subtypes and HLA-G, p53, VEGF and Ki67
Table 3 shows the correlation of tumor molecular subtypes and HLA-G, p53, VEGF and Ki67. There were significant differences in expressions of HLA-G, P53 and Ki67 among the subtypes (P = 0.035
Discussion
Generally, our 104 cases showed a similar distribution of breast cancer molecular subtypes as found in other studies [10], [19], [20], [21]. In our study, we did not find any significant association between molecular subtypes and traditional clinicopathological parameters such as tumor grade, size, nodal involvement and clinical stages.
However, our study did show that HLA-G expression was significantly higher in non-luminal than in luminal subtypes. Previously, it was demonstrated that aberrant
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A pilot study on Hla-G locus control region haplotypes and cervical intraepithelial neoplasias
2017, Human ImmunologyCitation Excerpt :Li et al. (2012) analyzing HLA-G expression in 22 normal cervical tissues, 14 cervical intraepithelial neoplasia (CIN) patients and 129 patients with squamous cell cervical cancer found that expression of HLA-G increases progressively from premalignant to malignant cervical lesions [9]. Similar findings were reported by Dong et al. (2012) by performing immune-histochemical analysis of HLA-G in cancer tissues based on the use of a monoclonal antibody HGY [32]. Taken together, all these results suggest that HLA-G polymorphisms and levels of expression play a role in HPV infection, cervical intraepithelial neoplasias and cervical cancer.
HLA-G variability and haplotypes detected by massively parallel sequencing procedures in the geographicaly distinct population samples of Brazil and Cyprus
2017, Molecular ImmunologyCitation Excerpt :HLA-G might inhibit immune responses when interacting with specific Natural Killer and T cell receptors such as KIR2DL4, ILT2 and ILT4 (Favier et al., 2010; LeMaoult et al., 2005; Rajagopalan and Long, 1999; Shiroishi et al., 2003; Colonna et al., 1997; Kamishikiryo and Maenaka, 2009 Shiroishi et al., 2003; Colonna et al., 1997; Kamishikiryo and Maenaka, 2009). Thus, the HLA-G molecule might influence the outcome of situations in which fine immune system modulation is required, such as during autoimmune diseases (Brenol et al., 2012; Aractingi et al., 2001; Rizzo et al., 2008), transplants (Misra et al., 2014; Crispim et al., 2008), cancer (Dunker et al., 2008; Cao et al., 2011; Dong et al., 2012) and pregnancy (Donadi et al., 2011; Larsen et al., 2010; Christiansen et al., 2012; Hylenius et al., 2004; Hviid, 2006; Nilsson et al., 2016). The interaction between HLA-G and KIR2DL4 may up regulate the expression of IFN-γ, which in turn mediates maternal vascular modifications (Goodridge et al., 2009; Tan et al., 2009).
HLA-F coding and regulatory segments variability determined by massively parallel sequencing procedures in a Brazilian population sample
2016, Human ImmunologyCitation Excerpt :The mechanisms underlying this lack of protein variability detected for HLA-F are not understood, mainly because HLA-F is located within the most variable region of the human genome. This phenomenon had already been observed for other non-classical class I genes such as HLA-G and HLA-E [14,17–20,80–82], which present tolerogenic and immune modulatory properties [22–25,27,83,84]. The HLA-F gene is also very conserved among primates evolution (including bonobo, gorilla, orangutan and chimpanzee), supporting the hypothesis of a critical role in the immune response [31].
Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: A pilot study
2013, Human PathologyCitation Excerpt :Another suggests that high Treg levels are preferentially associated with the basal phenotype, although high Treg infiltration correlated with shorter survival for HER-2+, luminal, and basal-type breast cancers [14]. A third study suggests that luminal breast cancers are more likely to contain large numbers of TILs than nonluminal breast cancers [15,16]. Complementing these findings, medullary breast cancer is a histologic subtype of invasive breast cancer characterized by large anaplastic tumor cells and an associated dense inflammatory infiltrate.
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