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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 251-256

Heat shock protein 90α in nipple discharge as a potential tumor marker for breast cancer


1 Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University; Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
2 Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
3 Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
4 Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
5 Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
6 Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

Date of Submission30-Jul-2021
Date of Decision25-Aug-2021
Date of Acceptance08-Sep-2021
Date of Web Publication27-Oct-2021

Correspondence Address:
Dr. Rong Ma
Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Jinan 250012, Shandong
China
Dr. Ya-Wen Wang
Department of Breast Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Jinan 250012, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_72_21

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  Abstract 


Heat shock protein 90α (HSP90α) has been confirmed to be upregulated in the blood in various types of tumors and may therefore serve as a potential tumor marker. However, whether HSP90α exists in nipple discharge remains unknown, and its expression and diagnostic value in nipple discharge remain unclear. In this study, the expression of HSP90α, carcinoembryonic antigen (CEA), and cancer antigen 153 in nipple discharge and blood from 128 patients was measured. Receiver operating characteristic curve was used to assess the diagnostic value of HSP90α. Further, its relationship with clinicopathological parameters of patients with breast cancer was analyzed. The results showed that the expression of HSP90α in nipple discharge was significantly higher in patients with breast cancer than in those with benign disease, and its diagnostic value was better than that of CEA. Combination of HSP90α and CEA showed better diagnostic efficacy than HSP90α or CEA alone. Moreover, the expression of HSP90α displayed a stepwise increase from benign lesions, followed by carcinoma in situ to invasive ductal carcinoma. HSP90α was positively correlated with Ki67 expression. However, there was no significant difference in the expression of HSP90α in blood between patients with breast cancer and benign disease. Further, the expression of HSP90α was higher in nipple discharge than in blood. In summary, HSP90α was upregulated in the nipple discharge of patients with breast cancer, and it may be related to the occurrence and progression of breast cancer. HSP90α in nipple discharge may serve as a potential diagnostic marker for breast cancer.

Keywords: Biomarker, breast cancer, diagnosis, heat shock protein 90α, nipple discharge


How to cite this article:
Wang YY, Liu C, Chen X, Ji J, Zhu SL, Sun Q, Zhang K, Zhu J, Zhao S, Wang YW, Ma R, Wang JL. Heat shock protein 90α in nipple discharge as a potential tumor marker for breast cancer. Chin J Physiol 2021;64:251-6

How to cite this URL:
Wang YY, Liu C, Chen X, Ji J, Zhu SL, Sun Q, Zhang K, Zhu J, Zhao S, Wang YW, Ma R, Wang JL. Heat shock protein 90α in nipple discharge as a potential tumor marker for breast cancer. Chin J Physiol [serial online] 2021 [cited 2021 Nov 27];64:251-6. Available from: https://www.cjphysiology.org/text.asp?2021/64/5/251/329364




  Introduction Top


Breast cancer is one of the most common cancers in the world, and its early diagnosis and treatment is key to improving prognosis. Nipple discharge is one of the main manifestations of breast disease. Although the lesions that cause nipple discharge are mostly benign, 7%–28.6% of patients are still diagnosed with breast cancer.[1],[2],[3],[4] For nipple discharge-associated breast cancer, imaging examinations are usually less sensitive, and mammography may miss 10%–40% of breast malignancies characterized by nipple discharge. Regarding patients with nipple discharge but lacking breast lumps, the detection rate is even lower.[5],[6] New detection methods are needed to distinguish between benign and malignant lesions resulting in nipple discharge.

Nipple discharge usually originates from the diseased area in the breast duct. The concentration of breast cancer-specific molecules in nipple discharge should be higher than that in other circulating body fluids, including serum and plasma. In addition, the process of collecting nipple discharge should be noninvasive.[7] Early diagnosis of breast cancer by detecting nipple discharge has great potential for clinical application.

Heat shock proteins (HSPs) are a family of cellular stress proteins, which are highly evolutionarily conserved.[8] Recently, studies have found that HSPs are closely related to the occurrence, development, and metastasis of tumors.[8] HSP90α, a subtype of HSPs, has been found to be aberrantly expressed in various malignant tumors.[9] Zhou et al. performed cell transcriptomics and serum proteomics analysis to screen hepatocellular carcinoma-associated biomarkers and found that HSP90α was upregulated in hepatocellular carcinoma cells, tissues, and serum. In particular, HSP90α was positively related to the metastasis of hepatocellular carcinoma.[10] A recent study reported that HSP90α expression was also significantly increased in the plasma of patients with breast cancer.[11] However, there were studies indicating no association between serum HSP90α levels and breast lesions or no differences in serum HSP90α levels between breast cancer cases and controls.[12],[13] Thus, Kazarian et al. claimed that serum HSP90α was possibly not a good early marker for breast cancer, although further investigation is warranted.[13] However, there have been no reports of HSP90α in nipple discharge. Whether HSP90α is present in nipple discharge and its clinical significance remain unclear. Herein, the expression of HSP90α in nipple discharge from 128 patients with nipple discharge was detected, and the diagnostic value of HSP90α was analyzed.


  Materials and Methods Top


Sample collection

This study included 128 patients with nipple discharge who were hospitalized in Qilu Hospital of Shandong University from January 2019 to March 2021. The pathological results of all patients were confirmed by two or more pathologists. Data on clinicopathological parameters (age, body mass index [BMI], tumor size, lymph node metastasis, etc.,) were collected for analysis. All studies were conducted in accordance with the principles of the Declaration of Helsinki and with the ethical standards of the responsible committee on human experimentation. All patients signed an informed consent form. This study was approved by the Ethics Committee of Qilu Hospital of Shandong University (KYLL-2018-096).

Detection of heat shock protein 90α, carcinoembryonic antigen, and cancer antigen 153 in nipple discharge and blood

Nipple discharge (50 μl) was collected in Eppendorf tubes and centrifuged to obtain supernatant for HSP90α, carcinoembryonic antigen (CEA), and cancer antigen 153 (CA153) detection. An EDTA-K2 anticoagulation tube was used to collect 2 ml of fasting peripheral blood. After centrifugation, the supernatant was collected to separate plasma that was subsequently used for HSP90α detection. Further, fasting peripheral blood (4 ml) was collected in a separating gel-filled coagulation tube. After centrifugation, the serum supernatant was used for the detection of CEA and CA153.

HSP90α expression in nipple discharge and plasma samples was quantitatively measured using a commercially available ELISA kit (Yantai Protgen Biotechnology Development Co., Ltd., Yantai, China) on an enzyme microplate reader (Huawei Delang Instrument Co., Wuxi, China) according to the manufacturer's instruction.[14]

The expression of CEA and CA153 in the nipple discharge and serum samples were quantitatively measured using an Electrochemiluminescence Immunoassay Kit (Roche Diagnostics, Indianapolis, IN, USA) on the Roche Cobas e601 analyzer.[1]

Statistical analysis

The difference between two groups was evaluated using t-test, and analysis of variance was performed for comparison between multiple groups. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of HSP90α and CEA. The cutoff values of HSP90α and CEA expression were determined by the ROC curve based on the Youden Index. P < 0.05 was considered to indicate statistical significance.


  Results Top


Heat shock protein 90α was upregulated in nipple discharge of patients with breast cancer versus benign disease

A total of 128 patients with nipple discharge were included in this study, of whom 32 (25%) were diagnosed with breast cancer (15 with invasive ductal carcinoma and 17 with carcinoma in situ) and 96 (75%) with benign breast lesions (72 with intraductal papilloma, 11 with duct ectasia, 7 with fibroadenoma, and 6 with breast hyperplasia) [Figure 1]. Compared with nipple discharge of patients with benign disease, HSP90α was upregulated in that of patients with breast cancer [[Figure 2]a; P < 0.0001]. We also detected the expression of CEA and CA153, which are common biomarkers of breast cancer, in benign and malignant nipple discharge. Our results showed that CEA expression was elevated in malignant discharge [[Figure 2]b; P = 0.0005], whereas CA153 showed no significant difference in benign and malignant discharge [[Figure 2]c; P = 0.1928].
Figure 1: Overview of the diagnostic information of patients with nipple discharge and the main design of the study.

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Figure 2: Expression of HSP90α, CEA, and CA153 in nipple discharge and the diagnostic value of HSP90α and CEA. (a-c) Compared with nipple discharge of patients with benign disease, HSP90α and CEA were upregulated in nipple discharge of patients with breast cancer. There was no significant difference in the expression of CA153 in benign and malignant nipple discharge (128 samples were available for HSP90α detection, 123 samples for CEA detection, and 124 samples for CA153 detection). (d) Receiver operating characteristic (ROC) curve analysis of HSP90α in the diagnosis of breast cancer. The AUC was 0.8268 (P < 0.0001). Based on the Youden Index, a diagnostic cutoff value of 281.7 ng/ml was found. The sensitivity and specificity of HSP90α in the diagnosis of breast cancer were 84.38% and 84.38%, respectively. (e) ROC curve analysis was performed to evaluate the diagnostic value of CEA in breast cancer. The AUC was 0.7086 (P = 0.0005). Based on the Youden Index, a diagnostic cutoff value of 494.5 ng/ml was found. CEA had a sensitivity of 51.61% and specificity of 90.22% for the diagnosis of breast cancer. (f) ROC curve analysis of the combination of HSP90α and CEA for the diagnosis of breast cancer. The AUC was 0.857 (P < 0.0001). AUC: Area under the curve, CEA: Carcinoembryonic antigen, CA153: Cancer antigen 153, HSP90α: Heat shock protein 90α.

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Diagnostic value of heat shock protein 90α in nipple discharge

ROC curve analysis indicated that the area under the curve (AUC) for HSP90α to distinguish benign and malignant nipple discharge was 0.8268 [[Figure 2]d; P < 0.0001]. The sensitivity and specificity of HSP90α in the diagnosis of breast cancer were 84.38% and 84.38%, respectively, with a cutoff value of 281.7 ng/ml. The AUC of CEA distinguishing benign and malignant nipple discharge was 0.7086 [[Figure 2]e; P = 0.0005], which was smaller than that of HSP90α. The sensitivity and specificity of CEA to detect breast cancer were 51.61% and 90.22%, respectively, with a cutoff value of 494.5 ng/ml.

To further improve the diagnostic efficacy, HSP90α and CEA were combined. Thus, the patients could be categorized as high risk (both HSP90α and CEA were higher than the cutoff), medium risk (HSP90α or CEA was higher than the cutoff), and low risk (both HSP90α and CEA were lower than the cutoff). The area under the ROC curve for combined HSP90α and CEA to distinguish breast cancer from benign disease was 0.857 [[Figure 2]f; P < 0.0001], which was higher than that for HSP90α and CEA alone. Specifically, among the 76 patients in the low-risk group, 72 (94.7%) had benign diseases, and only 4 (5.3%) had breast cancer. Among the 32 patients in the medium-risk group, 20 (62.5%) had benign diseases, and 12 had (37.5%) breast cancer. Further, among the 20 patients in the high-risk group, only 4 (20%) had benign diseases, and 16 (80%) had breast cancer. These results showed that concurrently high expression of HSP90α and CEA was indicative of breast cancer.

Relationship between heat shock protein 90α in nipple discharge and clinicopathological parameters

To explore the clinical significance of HSP90α, the relationship between HSP90α and clinicopathological parameters was further analyzed. First, patients with breast cancer were divided into carcinoma in situ and invasive ductal carcinoma, according to their histological types. The results showed that the expression of HSP90α showed a stepwise increase from benign lesions, followed by carcinoma in situ to invasive ductal carcinoma [[Figure 3]a; P < 0.0001]. Next, the relationship between HSP90α and clinicopathological parameters of patients with breast cancer was examined. The results showed a positive correlation between HSP90α and Ki67 expression [[Figure 3]b; r = 0.3639, P < 0.0480]. HSP90α tended to be highly expressed in patients negative for estrogen receptor (ER) or progesterone receptor (PR) expression [[Figure 3]c; P = 0.0556 or 0.0584, respectively]. However, HSP90α showed no significant correlation with patient age, BMI, tumor size, grade, lymph node metastasis, HER2 expression, molecular classification, T stage, N stage, or tumor stage [Figure 3]d, [Figure 3]e, [Figure 3]f, [Figure 3]g, [Figure 3]h, [Figure 3]i, [Figure 3]j, [Figure 3]k, [Figure 3]l.
Figure 3: Relationship between HSP90α expression in nipple discharge and clinicopathological parameters. (a) The expression of HSP90α showed an increasing trend from benign lesions, followed by carcinoma in situ to invasive ductal carcinoma (P < 0.0001). (b) HSP90α was positively correlated with Ki67 expression (r = 0.3639, P = 0.0480). (c) HSP90α tended to be highly expressed in patients with negative ER or PR expression (P = 0.0556 or P = 0.0584, respectively). (d-k) The expression of HSP90α in nipple discharge showed no significant correlation with grade, tumor size, LNM, HER2 expression, molecular subtype, T stage, N stage, and tumor stage. (l) In 128 patients with nipple discharge, the expression of HSP90α in nipple discharge was not significantly correlated with age and BMI. LNM: Lymph node metastasis, BMI: Body mass index, HSP90α: Heat shock proteins 90α, ER: Estrogen receptor, PR: Progesterone receptor.

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Heat shock protein 90α expression in nipple discharge was significantly higher than that in blood

The expression of HSP90α, CEA, and CA153 was also detected in blood. It was found that there was no significant difference in their expression in blood between patients with benign disease and those with breast cancer [Figure 4]a, [Figure 4]b, [Figure 4]c.
Figure 4: HSP90α expression in nipple discharge was higher than that in blood. (a-c) There was no significant difference in the expression of HSP90α, CEA, and CA153 in the blood of patients benign disease and breast cancer (116 samples were available for CEA detection, 115 samples for CA153 detection, and 47 samples for HSP90α detection). (d) HSP90α expression in nipple discharge and blood was concurrently detected in 47 patients. The results showed that the expression of HSP90α in nipple discharge was significantly higher than that in blood (P = 0.0003). (e) Among the 47 patients, 29 (61.7%) had higher HSP90α expression in nipple discharge than in blood. CEA: Carcinoembryonic antigen, CA153: Cancer antigen 153, HSP90α: Heat shock protein 90α.

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Moreover, the expression of HSP90α in the blood and nipple discharge of 47 patients was compared. Interestingly, our data showed that the expression of HSP90α in nipple discharge was significantly higher than that in blood [[Figure 4]d; P = 0.0003]. Specifically, among the 47 patients, 29 (61.7%) patients had a higher expression of HSP90α in nipple discharge than in blood [Figure 4]e.


  Discussion Top


Despite the fact that most nipple discharges are manifestations of benign breast diseases, there are still some patients with breast cancer who exhibit nipple discharge as a primary main symptom.[15],[16] However, traditional diagnostic methods of nipple discharge, such as cytology, ultrasound, ductography, ductoscopy, and MRI, have limited diagnostic value.[17] Therefore, there is an urgent need for more reliable diagnostic methods in clinical practice. Tumor marker detection for nipple discharge shows diagnostic advantages because it is fast, noninvasive, inexpensive, and without risk of radiation exposure. A number of studies have confirmed that detection of CEA in nipple discharge has a diagnostic value.[1],[18],[19] Gene methylation can also be used as a nipple discharge-based tumor marker to distinguish between benign and malignant breast tumors.[20] In recent years, benign and malignant nipple discharge was reportedly to show different miRNA expression profiles.[21] The expression of miR-4484, miR-K12-5-5p, and miR-3646 has proven to be upregulated and miR-4732-5p to be downregulated in nipple discharge of patients with breast cancer.[21]

HSPs are a class of highly conserved proteins with molecular chaperone characteristics, widely present in biological cells, and function to stabilize proteins and regulate cell metabolism.[22] Normal cells only secrete HSP90α under stress conditions such as hypoxia and tissue damage to promote tissue repair, whereas tumor cells constitutively secrete HSP90α to promote tumor cell movement, migration, and metastasis.[8] Studies have further reported that HSP90α was highly expressed in the serum of patients with non-small cell lung cancer, gastric cancer, and liver cancer, and that its expression was closely related to tumor grade, stage, and prognosis.[23],[24],[25],[26] However, there have been no reports on HSP90α expression in nipple discharge of patients with breast cancer. To the best of our knowledge, this study is the first to detect HSP90α expression in benign and malignant nipple discharge. We found that HSP90α was dramatically upregulated in the nipple discharge of patients with breast cancer, with a diagnostic cutoff value of 281.7 ng/ml, sensitivity of 84.38%, and specificity of 84.38%, to distinguish breast cancer from benign disease. The combination of HSP90α and CEA showed a higher AUC than HSP90α or CEA alone. Detection of HSP90α in nipple discharge showed promising diagnostic value to distinguish between benign and malignant lesions. High expression of both HSP90α and CEA was highly indicative of the risk of breast cancer. The combination of HSP90α and CEA was better than each single indicator in terms of cancer diagnosis.

In this study, it was found that HSP90α was significantly related to pathological subtypes. From benign lesions, followed by breast carcinoma in situ to invasive ductal carcinoma, the expression of HSP90α showed an increasing trend. HSP90α was positively correlated with Ki67 expression. This is consistent with the promoting effect of HSP90α on the proliferation and invasion of malignant tumors: HSP90α has previously been shown to induce high expression of the TCF12 protein through the CD91/IKK/NF-κB cascade reaction, to downregulate E-cadherin, and to stabilize and enhance the activity of MMP-2. MMP-2 could degrade extracellular matrix and contribute to tumor angiogenesis and tumor cell proliferation, thereby promoting tumor cell invasion.[27],[28] Negative ER and PR are important indicators of the aggressiveness and poor prognosis of breast cancer. Studies have shown that the expression of HSP90α in triple-negative breast cancer was higher than that in other types of breast cancer.[29] Our data showed that HSP90α tended to be highly expressed in patients with negative ER or PR expression. These results suggest that high expression of HSP90α in nipple discharge is related to high malignancy and poor prognosis of breast cancer. Our data indicated that HSP90α level in nipple discharge tended to be higher in patients with higher pathological grade, larger tumor size, lymph node metastasis, and advanced stage. However, these analyses did not reach statistical significance. The majority (25/32, 78.1%) of patients with breast cancer had a very early stage of cancer (Stages 0–I), and the sample size was relatively small. Thus, future studies with a larger sample size and patients at different stages are needed to address the association between HSP90α in nipple discharge and clinicopathological parameters.

HSP90α was reportedly upregulated in the blood of patients with malignancies, including hepatocellular carcinoma and breast cancer.[10],[11] However, our data suggested that plasma HSP90α expression showed no significant difference between patients with breast cancer (n = 11) and benign breast disease (n = 36). This may due to the fact that the majority (9/11, 81.8%) of patients had very-early-stage breast cancer (Stages 0–I), and the sample size was relatively small. More than half of the patients (6/11) were diagnosed with carcinoma in situ, rather than invasive carcinoma. Thus, further investigation is needed using larger multi-center cohorts, ideally with different stages and histological types, to further explore the diagnostic value of HSP90α in plasma of breast cancer.

Interestingly, the expression of HSP90α in nipple discharge was significantly higher than that in blood. Nipple discharge often originates from the cancerous area in the breast duct. Breast cancer-specific molecules can be concentrated and stably exist in nipple discharge, making it easier to detect the differential expression of HSP90α in nipple discharge.

The current study has some limitations. First, the sample size was small, and the samples were collected from a single hospital; thus, these findings need to be further confirmed in larger and independent cohorts. Second, the present study mainly focused on the diagnostic value of HSP90α in nipple discharge of patients with breast cancer. However, the prognostic value of HSP90α needs to be further investigated.


  Conclusion Top


In summary, HSP90α was upregulated in nipple discharge of patients with breast cancer, which may be related to tumor occurrence and progression. HSP90α in nipple discharge, especially combined with CEA, may serve as a potential diagnostic marker for breast cancer.

Acknowledgments

We would like to thank Yantai Protgen Biotechnology Development Co., Ltd, (Yantai, China) for technical help. We would like to thank Editage (www.editage.cn) for English language editing.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (Grant No. 81802406 and 81902698), Shandong Provincial Natural Science Foundation, China (Grant No. ZR2019BH061, ZR2018MH029 and ZR2019BH034), the Funding for New Clinical and Practical Techniques of Qilu Hospital of Shandong University (Grant No. 2019-1) and Shandong Co-Innovation Center of Classic TCM formula.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Zhao S, Mei Y, Wang J, Zhang K, Ma R. Different levels of CEA, CA153 and CA125 in milk and benign and malignant nipple discharge. PLoS One 2016;11:e0157639.  Back to cited text no. 1
    
2.
Louie LD, Crowe JP, Dawson AE, Lee KB, Baynes DL, Dowdy T, et al. Identification of breast cancer in patients with pathologic nipple discharge: Does ductoscopy predict malignancy? Am J Surg 2006;192:530-3.  Back to cited text no. 2
    
3.
Montroni I, Santini D, Zucchini G, Fiacchi M, Zanotti S, Ugolini G, et al. Nipple discharge: Is its significance as a risk factor for breast cancer fully understood? Observational study including 915 consecutive patients who underwent selective duct excision. Breast Cancer Res Treat 2010;123:895-900.  Back to cited text no. 3
    
4.
Zhao S, Gai X, Wang Y, Liang W, Gao H, Zhang K, et al. Diagnostic values of carcinoembryonic antigen, cancer antigen 15-3 and cancer antigen 125 levels in nipple discharge. Chin J Physiol 2015;58:385-92.  Back to cited text no. 4
    
5.
Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: An analysis of 27,825 patient evaluations. Radiology 2002;225:165-75.  Back to cited text no. 5
    
6.
Tice JA, Miike R, Adduci K, Petrakis NL, King E, Wrensch MR. Nipple aspirate fluid cytology and the Gail model for breast cancer risk assessment in a screening population. Cancer Epidemiol Biomarkers Prev 2005;14:324-8.  Back to cited text no. 6
    
7.
Sauter ER, Wagner-Mann C, Ehya H, Klein-Szanto A. Biologic markers of breast cancer in nipple aspirate fluid and nipple discharge are associated with clinical findings. Cancer Detect Prev 2007;31:50-8.  Back to cited text no. 7
    
8.
Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat shock proteins and cancer. Trends Pharmacol Sci 2017;38:226-56.  Back to cited text no. 8
    
9.
Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 2017;18:345-60.  Back to cited text no. 9
    
10.
Zhou Y, Deng X, Zang N, Li H, Li G, Li C, et al. Transcriptomic and proteomic investigation of HSP90A as a potential biomarker for HCC. Med Sci Monit 2015;21:4039-49.  Back to cited text no. 10
    
11.
Hou Q, Chen S, An Q, Li B, Fu Y, Luo Y. Extracellular Hsp90α promotes tumor lymphangiogenesis and lymph node metastasis in breast cancer. Int J Mol Sci 2021;22:7747.  Back to cited text no. 11
    
12.
Zagouri F, Sergentanis TN, Provatopoulou X, Kalogera E, Chrysikos D, Lymperi M, et al. Serum levels of HSP90 in the continuum of breast ductal and lobular lesions. In Vivo 2011;25:669-72.  Back to cited text no. 12
    
13.
Kazarian A, Blyuss O, Metodieva G, Gentry-Maharaj A, Ryan A, Kiseleva EM, et al. Testing breast cancer serum biomarkers for early detection and prognosis in pre-diagnosis samples. Br J Cancer 2017;116:501-8.  Back to cited text no. 13
    
14.
Zhao Q, Miao C, Lu Q, Wu W, He Y, Wu S, et al. Clinical significance of monitoring circulating free DNA and plasma heat shock protein 90alpha in patients with esophageal squamous cell carcinoma. Cancer Manag Res 2021;13:2223-34.  Back to cited text no. 14
    
15.
Vargas HI, Romero L, Chlebowski RT. Management of bloody nipple discharge. Curr Treat Options Oncol 2002;3:157-61.  Back to cited text no. 15
    
16.
Seltzer MH. Breast complaints, biopsies, and cancer correlated with age in 10,000 consecutive new surgical referrals. Breast J 2004;10:111-7.  Back to cited text no. 16
    
17.
Alcock C, Layer GT. Predicting occult malignancy in nipple discharge. ANZ J Surg 2010;80:646-9.  Back to cited text no. 17
    
18.
Inaji H, Yayoi E, Maeura Y, Matsuura N, Tominaga S, Koyama H, et al. Carcinoembryonic antigen estimation in nipple discharge as an adjunctive tool in the diagnosis of early breast cancer. Cancer 1987;60:3008-13.  Back to cited text no. 18
    
19.
Wang G, Qin Y, Zhang J, Zhao J, Liang Y, Zhang Z, et al. Nipple discharge of CA15-3, CA125, CEA and TSGF as a new biomarker panel for breast cancer. Int J Mol Sci 2014;15:9546-65.  Back to cited text no. 19
    
20.
de Groot JS, Moelans CB, Elias SG, Jo Fackler M, van Domselaar R, Suijkerbuijk KP, et al. DNA promoter hypermethylation in nipple fluid: A potential tool for early breast cancer detection. Oncotarget 2016;7:24778-91.  Back to cited text no. 20
    
21.
Zhang K, Zhao S, Wang Q, Yang HS, Zhu J, Ma R. Identification of microRNAs in nipple discharge as potential diagnostic biomarkers for breast cancer. Ann Surg Oncol 2015;22 Suppl 3:S536-44.  Back to cited text no. 21
    
22.
Calderwood SK. Heat shock proteins and cancer: Intracellular chaperones or extracellular signalling ligands? Philos Trans R Soc Lond B Biol Sci 2018;373:20160524.  Back to cited text no. 22
    
23.
Lee HW, Kim KM. Clinical significance of heat shock protein 90α expression as a biomarker of prognosis in patients with gastric cancer. Niger J Clin Pract 2019;22:1698-705.  Back to cited text no. 23
[PUBMED]  [Full text]  
24.
Fu Y, Xu X, Huang D, Cui D, Liu L, Liu J, et al. Plasma heat shock protein 90alpha as a biomarker for the diagnosis of liver cancer: An official, large-scale, and multicenter clinical trial. EBioMedicine 2017;24:56-63.  Back to cited text no. 24
    
25.
Shi Y, Liu X, Lou J, Han X, Zhang L, Wang Q, et al. Plasma levels of heat shock protein 90 alpha associated with lung cancer development and treatment responses. Clin Cancer Res 2014;20:6016-22.  Back to cited text no. 25
    
26.
Sims JD, McCready J, Jay DG. Extracellular heat shock protein (Hsp) 70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 2011;6:e18848.  Back to cited text no. 26
    
27.
Zou M, Bhatia A, Dong H, Jayaprakash P, Guo J, Sahu D, et al. Evolutionarily conserved dual lysine motif determines the non-chaperone function of secreted Hsp90alpha in tumour progression. Oncogene 2017;36:2160-71.  Back to cited text no. 27
    
28.
Chen WS, Chen CC, Chen LL, Lee CC, Huang TS. Secreted heat shock protein 90α (HSP90α) induces nuclear factor-κB-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J Biol Chem 2013;288:9001-10.  Back to cited text no. 28
    
29.
Moriya C, Taniguchi H, Nagatoishi S, Igarashi H, Tsumoto K, Imai K. PRDM14 directly interacts with heat shock proteins HSP90α and glucose-regulated protein 78. Cancer Sci 2018;109:373-83.  Back to cited text no. 29
    


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