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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 14
| Issue : 1 | Page : 14-20 |
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Association of Augmented Immune-Staining of G-Quadruplex Tertiary DNA Structure in Chemo-Tolerant TNBC with Downregulation of WNT/Epidermal Growth Factor Receptor Pathway receptor Genes: A Pilot Clinicopathological Study
Saimul Islam1, Mukta Basu1, Anup Roy2, Neyaz Alam3, Chinmay Kumar Panda1
1 Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
2 Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India
3 Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| Date of Submission | 22-Mar-2022 |
| Date of Decision | 09-Jun-2022 |
| Date of Acceptance | 10-Jun-2022 |
| Date of Web Publication | 16-Jan-2023 |
Correspondence Address:
Dr. Chinmay Kumar Panda
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jrcr.jrcr_23_22
Purpose: The aim of the study is to understand the involvement of G-Quadruplex (G-Q) structures in altering the expression profile of WNT/epidermal growth factor receptor (EGFR) pathway receptor genes in chemo-tolerant Triple Negative Breast Cancer (TNBC) samples. Materials and Methods: At first, Gene Expression Omnibus datasets were mined where the expression profile of WNT/EGFR pathway genes in TNBC samples and MDA-MB-231, a TNBC cell line, were checked in response to doxorubicin, a chemotherapeutic drug. Next, to unveil the probable mechanism of regulation, the presence of G-Q structure was checked in in silico study and later validated by immunohistochemical analyses in our pool of sample. These observed results were correlated with patient's demography and survival status. Results: Expression of the receptors (FZD7, LRP6, EGFR) of the WNT/EGFR pathway were found to be differentially expressed in TNBC samples; further emphasized in our samples (n = 61). Notably, these G-Q structures were found in the promoter region of the WNT pathway receptor genes (FZD7, LRP6, and EGFR). Validating in our patient sample pool, a significant increase in G-Q immunostaining was observed in samples, after neoadjuvant chemotherapy (NACT) samples (n = 17) than the pretherapeutic samples (n = 44). Similar pattern of G-Q immunostaining was noticed in doxorubicin-treated MDA-MB-231 cell line. Intriguingly, low staining of G-Q among the pretherapeutic samples, but NACT TNBC samples, was found to be significantly correlated with lymph node metastasis. Conclusions: This study showed that the augmented immunostaining of G-Q structure might have an important involvement in regulating the expression pattern of the WNT/EGFR pathway genes in response to doxorubicin treatment of TNBC. Keywords: G-Quadruplex structure, neoadjuvant chemotherapy, poor prognosis, triple-negative breast cancer
How to cite this article:
Islam S, Basu M, Roy A, Alam N, Panda CK. Association of Augmented Immune-Staining of G-Quadruplex Tertiary DNA Structure in Chemo-Tolerant TNBC with Downregulation of WNT/Epidermal Growth Factor Receptor Pathway receptor Genes: A Pilot Clinicopathological Study. J Radiat Cancer Res 2023;14:14-20 |
How to cite this URL:
Islam S, Basu M, Roy A, Alam N, Panda CK. Association of Augmented Immune-Staining of G-Quadruplex Tertiary DNA Structure in Chemo-Tolerant TNBC with Downregulation of WNT/Epidermal Growth Factor Receptor Pathway receptor Genes: A Pilot Clinicopathological Study. J Radiat Cancer Res [serial online] 2023 [cited 2023 Jun 7];14:14-20. Available from: https://www.journalrcr.org/text.asp?2023/14/1/14/367850 |
| Introduction | |  |
Triple-Negative Breast Cancer (TNBC), a most aggressive subtype of breast cancer (BC), can be defined as reduced expression of estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor.[1] Globally, it accounts for about 15%–20% of the total BC patients, whereas in Indian subcontinents its frequency hiked to ~25%–30% of the BC patient.[2],[3],[4] Chemotherapy is still considered to be the major treatment protocol, besides surgery, and radiotherapy; although it registers worst prognosis as well as high disease relapse.[5],[6] In chemotherapeutic treatment regime, neoadjuvant chemotherapy (NACT) is mainly administered to shrink the size of the primary tumor, increasing the feasibility of surgery and prognosis of the disease.[7] The residual tumors, called the chemotolerant cells, were supposed to be the primary, but not the sole, players of chemotolerance.[8] Doxorubicin, an anthracycline chemotherapeutic drug used to treat TNBC, mainly exhibits its anti-tumor activity through intercalating DNA as well as inhibits Topoisomerase II activity.[9],[10] Furthermore, the anthracycline group of drugs could preferentially interact with nuclease hypersensitive sites of open chromatin area due to its altered conformation.[11],[12],[13] In one preceding study, the doxorubicin-tolerant BC cells showed low proliferation index and CD44 positive stem cell prevalence.[14] It can be substantiated that the reduced expression of CD44 might be due to reduced expression of its transcriptional activator beta-catenin, an effector protein of WNT pathway[15] (Islam et al., 2020). In another study, down regulation of receptors (FZD7, LRP6, epidermal growth factor receptor [EGFR]) associated with activation of beta-catenin were also seen in chemo-tolerant TNBC.[16] The up regulation of the antagonists was proven to be due to promoter hypomethylation of the gene.[17] Differential expression of genes including the WNT/EGFR pathway in chemo-tolerant TNBC has also been reported in different data sets.[18],[19],[20] However, no correlation has yet been made in different data sets to find out the consensus altered expression of the WNT/EGFR receptor genes, if any. In addition, the mechanism of reduced expression of the receptors (FZD7, LRP6, and EGFR) in chemo-tolerant TNBC is still unknown.
Apart from epigenetic mechanism, the conformation of different chromosomal regions due to specific DNA sequence like G-Quadruplex (G-Q) structure has important role in the regulation of different genes.[21] It was evident that doxorubicin could stabilize the G-Q structure in 5'-flanking regions proximal to c-MYC gene for its inactivation.[22],[23] Furthermore, the association of G-Q structure with the regulation of CD44 and CD133 expression in chemo-resistant of breast and colorectal tumor stem cell population has been reported.[24],[25] However, importance of G-Q structure in regulation of receptors and antagonists of WNT/EGFR pathway in chemo-tolerance of TNBC, if any, still remains uncharted.
Thus, in this study correlation between different data sets and a previously published data, accounting for the expression status of receptor genes of WNT/EGFR pathway in chemo-tolerant TNBC was drawn at first, to find out a harmonious trend in these metachronous studies, if any. Then, G-Q profile in pretherapeutic (n = 44) and NACT (n = 17) TNBC samples of this study was analyzed followed by validation in a doxorubicin treated TNBC cell line MDA-MB-231 to mimic the NACT molecular profile. G-Q immunostaining profile was further associated statistically with different clinicopathological parameters and patient's prognosis. In conclusion, this study showed a consensus expression profile of the receptor genes of this pathway among the different data sets as well as in the sample pool, used here. In addition, the increased nuclear immunostaining of G-Q structure showed importance in chemo-tolerance of TNBC.
| Materials and Methods | | |
Analysis gene expression omnibus data sets
High throughput molecular abundance data from Gene Expression Omnibus (GEO) had been retrieved to analyze the differential expression of the candidate genes in the effect of chemotherapeutic drugs. For evaluating the effect of doxorubicin drug in the primary TNBC tissues, three expression array studies: GSE43816, GSE21974, and GSE18728 were used, where primary tumor tissue, both before and after treatment with chemotherapeutic drugs were analyzed.[18],[19],[20] All the three studies were compared and the common genes were sieved out. A similar work had been done in MDA-MB 231 cells where another three expression array studies: GSE116441, GSE54326, and GSE39042 were used.[25],[26],[27],[28] The common genes from both the pool, TNBC and MDA-MB-231 were compared and the common gene set was extracted whose expression was supposed to be affected by the chemotherapeutic drug.
Patient's demography
Based on analysis of molecular marker (ER, PR, and HER2), 44 pretherapeutic and 17 NACT TNBC samples along with their corresponding adjacent normal tissue were collected from two unrelated patients pool from the hospital section of our institute during 1999–2015, as discussed previously.[15] The study was done with appropriate approval of the Institutional Ethical Committee and has been performed in accordance with the ethical standards as laid down in the 1964 (Declaration of Helsinki). This study was done with informed consent from the patients and has been performed in accordance with the ethical standards as laid down in the 1964 (Declaration of Helsinki). A proper written consent for publication has been taken from either the patient or their guardian. All the TNBC samples were staged and graded according to the Union for International Cancer Control (UICC) tumor node metastasis classification. In these sample pools, used in a previous study,[15] 47%–52.9% of the NACT samples showed reduced expression of the receptors, in comparison to pretherapeutic samples. Details clinicopathological parameters of both pretherapeutic and NACT samples are shown in [Table S1][Additional file 1].
Immunohistochemistry analysis
The immunostaining of G-Q structure was analyzed by immunohistochemistry (IHC) according to standard procedure.[29] The primary antibodies of G-Q (1H6, MABE1126) and appropriate HRP conjugated secondary antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Diaminobenzidine (sc-24982, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used for color development, and hematoxylin used as counter stain. The staining intensity (1 = weak, 2 = moderate, 3 = strong) and percentage of positive cells (<1 = 0, 1–20 = 1, 20–50 = 2, 50–80 = 3, and >80 = 4) were detected by two independent observers and by combining the two scores, final evaluation of expression was done (0–2 = low, 3–5 = intermediate, 6–7 = high).[30] The nuclear and cytoplasmic staining patterns of the proteins in both primary tumors and ducts of normal breast tissue samples were determined under a Bright field microscope (Leica, Germany). Then, the staining patterns in primary tumors were compared with the staining patterns of the ducts of the normal breast samples.
Immunocytochemistry analysis
The TNBC cell lines MDA-MB-231 were obtained from the National Centre for Cell Sciences, Pune, India, with proper STR profiling of the cell lines. According to the supplied protocol, MDA MB 231 was cultured in Leibovitz's L-15 (Himedia, India) Medium, supplemented with 10% FBS and 1% penicillin/streptomycin at 37°C, 5% CO2. These cells were treated with different concentration of doxorubicin drug (0.2 μM, 0.346 μM IC50 and 0.6 μM) and the cells were cultured at 37℃ for 48 h. For immunocytochemistry, cells were incubated with the G-Q antibody after washing with ×1 PBS. Then, fluorescein isothiocyanate–conjugated secondary antibodies (sc-2010) were used for the detection of protein, and 4′,6-diamidino-2-phenylindole (sc-3598) was used to stain the nucleus (Santa Cruz Biotechnology).[31]
Statistical analysis
Fisher's exact test was used for the analysis of contingency table to find the differences among proportions. Survival analysis was done using Kaplan–Meier method and log-rank test was used to compare the survival patterns of groups. Overall survival was measured from the time of registration to the hospital to the date of most recent follow-up, recurrence, metastasis, or death (up to 5 years). All the statistical analyses were performed using statistical programs Epi Info 6.04 (Centers for Disease Control and Prevention, Atlanta, Georgia, USA), SPSS 10.0 (IBM, NY, USA) software. The t-test was performed to compare the expressions of genes between pretherapeutic and NACT-treated samples. P < 0.05 was considered to be statistically significant.
| Results | | |
In silico analysis of WNT and epidermal growth factor receptor pathway in chemo-tolerant TNBC
In in silico analysis, three public microarray data sets of primary TNBC and three data sets of a TNBC cell line MDA-MB-231 showed consensus expression of 11316 genes between doxorubicin treated and untreated groups of both primary tumor and cell line [Figure 1]a, [Figure 1]b, [Figure 1]c. Among the consensus expression of genes, the WNT/beta-catenin stem cell renewal pathway receptors (FZD7 and LRP6) and EGFR signaling pathway receptor (EGFR) were selected due to their significant association with chemo-tolerant TNBC as seen in one previous study.[15] The overall data sets of primary tumor and the cell line showed reduced expression of FZD7, LRP6, and EGFR genes in chemo-tolerant TNBC [Figure 1]d. A similar trend of the expression pattern of these genes was found in chemo-tolerant TNBC in the past studies.[15] | Figure 1: In silico analysis of public microarray expression data sets in chemotherapy drug treated/untreated TNBC samples and TNBC cell line MDA-MB-231: In silico analysis of microarray expression dataset of (a) three TNBC primary BC samples and (b) three TNBC cell line MDA-MB-231, before and after treatment with chemotherapeutic drugs. (c) Venn diagram represents the number of common genes found from both the sample pool. (d) Table represents mean logarithmic fold change of the candidate genes in all the six datasets. Histograms replicate the data given in the table, showing under expression of FZD7, LRP6, and EGFR after the chemotherapeutic drug treatment. TNBC: Triple Negative Breast Cancer,, EGFR: Epidermal growth factor receptor
Click here to view |
Increased immunostaining of G-quadruplex structure in neo-adjuvant chemotherapy TNBC samples
Therefore, to divulge any possible involvement of G-Q structure in downregulation of WNT/EGFR pathway receptors (FZD7, LRP6, and EGFR); immunohistochemical staining of G-Q structure was analyzed in both pre-therapeutic and NACT TNBC samples. In normal breast duct, luminal and myoepithelial cells showed predominant nuclear staining of G-Q structure [Figure 2]a and [Figure 2]b. However, a significant increase in staining frequency of G-Q structure was seen in NACT samples (58.8%, 10/17) than the pretherapeutic TNBC samples (38.6%, 17/44) [Figure 2]c, [Figure 2]d, [Figure 2]e. | Figure 2: Immunohistochemical analysis of the G-Quadruplex in pretherapeutic and NACT samples: Representative immunohistochemical staining pattern of Negative control sample (NC) without primary antibody. (a) normal breast tissue. (b) pretherapeutic (c) and NACT samples. (d) Blue arrow denoted nuclear expression. (e) Dot plot represents frequency of G-Quarduplex staining positive cells in the in normal breast tissue, pretherapeutic and NACT samples. Horizontal lines represent mean value of staining positive cells with error bar in the respective groups. NACT: Neo-adjuvant chemotherapy
Click here to view |
Validation of the G-quadruplex immunostaining profile in neoadjuvant chemotherapy TNBC samples in a chemo-tolerant mimic TNBC cell line
To validate the G-Q structure immunohistochemical staining in NACT TNBC samples, immunocytochemical staining of G-Q structure was performed in MDA-MB-231 cell line after treatment with doxorubicin to mimic the NACT TNBC. The staining of G-Q structure was found to gradually increase with doxorubicin concentrations [Figure 3], suggesting stabilization of G-Q structure. | Figure 3: Immunocytochemical analysis of the G-Quadruplex doxorubicin treated TNBC cell line MDA-MB-231: Representative immunocytochemical staining shows gradual increase of G-Quardruplex staining with doxorubicin concentration. TNBC: Triple Negative Breast Cancer
Click here to view |
Association of G-quadruplex immunostaining with the expression pattern of WNT regulatory genes
In-depth in silico analysis unveiled localization of G-Q structure at Transcriptional start sites of FZD7 (−843 to −811; −809 to − 791; −700 to −671), LRP6 (−495 to −467), and EGFR (−341 to − 311; −51 to −26; 389–411) [Figure 4]a, [Figure 4]b, [Figure 4]c. | Figure 4: Schematic representation of G-Quarduplex location with respect to TSS on proximal region of (a) FZD7, (b) LRP6 (c) EGFR. The location was predicted using QuadBase2 web server (http://quadbase.igib.res.in/). EGFR: Epidermal growth factor receptor, TSS: Transcriptional start sites
Click here to view |
After comparing the staining intensity of G-Q tertiary structure and expression pattern of WNT receptor genes, it was observed that the low staining of G-Q structure was found to be positively correlated with the high expression patterns of oncogenic receptors, LRP6, FZD7, and EGFR in pre-therapeutic samples [Table 1]a. However, no such association was found among the NACT samples [Table 1]a. Therefore, it is an indication that chemotherapeutic drugs might have an important role in regulating the structure of G-Q and hence, the expression of protein-coding genes.
Clinicopathological and prognostic importance
The pretherapeutic patients with low staining of G-Q structure showed significant association with poor prognosis of the disease [Figure 5]a. However, no such association was observed in the NACT samples [Figure 5]b. The clinicopathological and prognostic importance of G-Q structure was analyzed by different statistical analysis like univariate and Kaplan–Meier survival methods in pretherapeutic and NACT TNBC samples. Low staining of G-Q structure showed significant association with nodal status of the pretherapeutic TNBC samples [Table 1]b. | Figure 5: Kaplan–Meier survival analysis in pretherapeutic and NACT TNBC patients: Kaplan–Meier 5-year survival probability curves of patients with high/low staining of G-Quadruplex in (a) pretherapeutic TNBC patients and (b) NACT TNBC patients. (N: sample size). TNBC: Triple Negative Breast Cancer, NACT: Neo-adjuvant chemotherapy
Click here to view |
| Discussion | | |
In this study, the importance of G-Q structure in alteration of the expression profile of receptor genes of WNT/EGFR pathway (among different data sets) in chemo-tolerant TNBC was focused. Comparatively reduced expression of the receptors (FZD7, LRP6, and EGFR) was observed in NACT TNBC samples than the pretherapeutic samples in different GEO expression data sets as well as in our data, indicated their importance in chemo-tolerance of TNBC.
Therefore, the formation or stabilization of G-Q DNA structures, a possible mechanism of regulation of these gene sets was evaluated. Likewise, increase in G-Q staining in the NACT samples contrary to the pretherapeutic samples suggests its importance in chemo-tolerance of TNBC, possibly due to stabilization of G-Q structures by doxorubicin through adduct formation.[21] Therefore, the reduced expression of the receptors in NACT samples as well as in doxorubicin-treated MDA-MB-231 cell line can be justified by stabilization of G-Q structures, present in proximity to the promoter region of these genes, thereby slowing down their transcriptional process.[31] On the other hand, G-Q was also found in the distal region of the promoter of few genes might not have a similar effect,[32],[33] further studied will expose the real effect.
On the other hand, poor clinical outcome of the pretherapeutic TNBC samples has been observed to be associated with BC patients possessing (i) low immunostaining profile of G-Q (ii) low immunostaining profile of G-Q and lymph node positivity. The absence of such association in NACT TNBC samples might be due to drug-induced stabilization of G-Q, leading to modulation in expression of the genes associated with cellular proliferation like WNT/EGFR pathway as seen in past studies.[14] The decrease in proliferation index of the NACT TNBC samples compared to the pretherapeutic samples, in past studies,[13] can be correlated well with the G-Q structures as observed in this study.
| Conclusions | | |
This study revealed that the consensus expression profile of the receptor genes of WNT/EGFR pathway in the entire data sets in chemo-tolerant TNBC might be due to the stabilization of G-Q structure.
Financial support and sponsorship
The work was financially support by University Grants Commission-National Eligibility Test Fellowship grant (Sr.No. 2061430780, Ref No.: 22/06/2014 [i] EU-V) to Ms. Mukta Basu. National Academy of Science (2020), India Senior Scientist Platinum Jubilee Fellowship to C.K.P.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1]
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