Open Access

Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients

  • Authors:
    • Tao Sun
    • Daqing Jiang
    • Liang Zhang
    • Qinglong Su
    • Wanli Mao
    • Cui Jiang
  • View Affiliations

  • Published online on: November 23, 2015     https://doi.org/10.3892/ol.2015.3960
  • Pages: 575-583
  • Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer is one of the most prevalent types of cancer in women and contributes to 32% of all female cancer cases. Cathepsins, a family of proteins, are known to have a critical role in human cancers. However, previous studies on the systematic analysis of the role of cathepsin family members in breast cancer are limited. The aim of the present study was to identify biological markers to predict prognosis and treatment response of breast cancer patients, as well as to elucidate novel therapeutic targets. The present study analyzed the expression of six members of cathepsin family, including cathepsins B, G, D, K, L and V in 188 breast cancer tissue specimens using immunohistochemistry. The data showed that all members of the tested cathepsin families featured cytoplasmic staining. Notably, expression of cathepsin L was associated with advanced tumor stages, while cathepsins B and K expression levels were associated with positive estrogen receptor expression; in addition, cathepsin K expression was also demonstrated to be associated with progesterone receptor expression. Cathepsins V and D expression levels were found to be associated with breast cancer metastasis, while the expression levels of cathepsins B and D were associated with poor disease‑free survival in breast cancer patients. In addition, univariate analysis demonstrated that breast cancer metastasis to the bone and the expression of cathepsin B protein were associated with poor disease‑free survival. In conclusion, the results of the present study indicated that the altered expression of cathepsins, in particular cathepsins B and D, contributed to the progression of breast cancer and poor disease-free survival in breast cancer patients.

Introduction

Breast cancer is the most prominent health problem for women worldwide, affecting one in eight women (13). Over the past three decades, there have been numerous advances for breast cancer patients, including earlier detection, increased treatment options and more prevention strategies. However, breast cancer remains to be the second highest cause of cancer-associated mortality in women (1,2). Breast cancer progression, such as metastasis to distant organs, is significantly associated with cancer-associated mortality (1,3). Thus, it is crucial to identify biomarkers to predict prognosis and treatment response, and elucidate novel therapeutic targets of breast cancer.

Proteolytic activity has been reported to be significantly associated with cancer metastasis and altered proteolytic activities was also found to cause a wide range of diseases, including cancer (4). To date, ~500–600 proteases have been identified in the human genome (5). Among them, up to 60 are lysosomal proteases and cathepsins; cathepsins are a group of lysosomal or cysteine proteases, which include 16 members in humans (69). Expression of cathepsins has been shown to be upregulated in various types of human cancers (1012); in addition, altered expression of cathepsins has been associated with tumor angiogenesis, proliferation and invasion (13,14). For example, during cancer progression, translocated or secreted cathepsins were reported to promote tumor cell invasion and metastasis (14).

However, different cathepsins may have different roles in human cancers. Cathepsins B and D were often found to be overexpressed and associated with invasive and metastatic phenotypes of various types of human cancers (1518). However, the role of each member of the cathepsin family in breast cancer remains to be fully elucidated and to date there have been a limited number of studies on the function of different members of the cathepsin family in breast cancer. A small number of previous studies have reported the altered expression of cathepsins D, B and E in breast carcinogenesis (1923). In addition, previous studies have reported that cathepsin D was overexpressed in invasive ductal carcinoma compared with its expression in lobular carcinoma of the mammary glands (21,24,25). Furthermore, overexpression of cathepsin D was associated with lymph node metastasis of breast invasive ductal carcinoma (21).

Notably, the design of small molecular inhibitors targeting cathepsins is a strategy that has been used previously against human cancer, among other diseases (26). Each cathepsin has a different cleavage bond-specificity for substrate proteins, thus allowing for the development of cathepsin-specific inhibitors for targeting different family members (26,27). Such inhibitors include E-64, leupeptin and antipain (26,28,29). These inhibitors are able to selectively suppress cathepsin activity and inhibit tumor growth. For example, anti-cathepsin B and D have been demonstrated to have efficacy in cancer therapy (16,27,30).

Detailed comparison studies of the expression of different members of the cathepsin family in breast cancer are limited. Therefore, the aim of the present study was to analyze the expression of six important members of cathepsin family, including cathepsins B, D, G, K, L and V, in breast cancer tissue specimens. In addition, the expression of these cathepsins was compared with that of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and vascular endothelial growth factor (VEGF). The expression of these proteins was then analyzed for associations with the clinicopathological data of patients and breast cancer patient survival rates. These data may allow for the development of novel therapies for the treatment of breast cancer patients. In addition, the results of the present study may elucidate cathepsins that have a more dominant role in breast cancer compared with other family members, thus providing evidence for their use in predicting the prognosis of breast cancer patients as well as the development of novel cathepsin-specific treatment options.

Materials and methods

Patient specimens

In the present study, tissue specimens were retrospectively collected from 188 breast cancer patients who underwent treatment at the Liaoning Cancer Hospital and Institute (Liaoning, China). All patients were pathologically diagnosed with breast invasive ductal carcinoma. The present study was approved by the hospital review board of the Liaoning Cancer Hospital and Institute and each patient provided written informed consent for their participation in the study. In addition, follow-up data regarding survival and adverse effects were also collected for the present study at follow-up clinic visits or via phone interview. The detailed clinicopathological data, including age, gender, pathological type, clinical symptoms and stage, lymph node and distant metastasis, expression of estrogen receptor (ER), progesterone receptor (PR) and erythroblastic leukemia viral oncogene homolog 2 (erbB2), menstrual status and laboratory tests, were collected from the patients' medical records.

Immunohistochemistry

All tissue specimens were fixed in 4% paraformaldehyde (Sigma-Aldrich, St. Louis, MO, USA) and then dehydrated and embedded in paraffin (Sigma-Aldrich). For immunohistochemistry, the tissue blocks were cut into 4-cm-thick sections and placed in vertical plastic boxes until further use. The sections were dewaxed in analytical reagent (AR) grade xylene AR and rehydrated through graded alcohol series (AR grade; 100, 95, 90, 80 and 70%). For antigen retrieval, the sections were heated in a citrate buffer (0.01 M; pH 6.0) using a microwave oven (800 W; Haier, Qingdao, China) for 30 min at 93°C. Following washing three times in phosphate-buffered saline (PBS; Abcam, Cambridge, MA, USA) for 10 min each, the sections were incubated with 3% bovine serum albumin (Abcam) at 37°C for 30 min. Tissues were then incubated with primary antibodies, including antibodies against cathepsin B (rabbit anti-human polyclonal; 1:50 dilution; cat no. 12216-1-AP), cathepsin K (rabbit anti-human polyclonal; 1:100 dilution; cat no. 11239-1-AP), cathepsin D (mouse anti-human monoclonal; 1:200 dilution; cat no. 2926S), cathepsin G (rabbit anti-human polyclonal; 1:600 dilution; cat no. ab64891), cathepsin L (mouse anti-human monoclonal; 1:100 dilution; cat no. ab6314), cathepsin V (mouse anti-human monoclonal; 1:200 dilution; cat no. ab24508), VEGF (mouse anti-human monoclonal; 1:200 dilution; cat no. ab464154) and RECK (mouse anti-human monoclonal; 1:40 dilution; cat no. 611512) overnight at 4°C. Cathepsin B and K were obtained from Proteintech (Chicago, IL, USA); cathepsin D, G, L and V, and VEGF were obtained from Abcam; and RECK was obtained from Becton Dickinson (Franklin lakes, New Jersey, USA). The following day, the sections were washed three times with PBS and then further incubated with the corresponding secondary antibodies (Abcam) at 37°C for 30 min. For color reactions, the sections were washed again with PBS for three times of 5 min each and then stained with a diaminobenzidine solution (Abcam) for up to 5 min. Protein expression in tumor cells was assessed for proportion and intensity score independently by two experienced pathologists. Specifically, the intensity score was obtained by the average intensity of positive cells, which was scored as follows: 0, none; 1, weak; 2, intermediate; and 3, strong. The proportion score was determined according to the proportion of positive cells as follows: 0, none; 1, ≤10%; 2, 11–25%; 3, 26–50%; and 4, >50%. The final score for each protein was calculated by adding the scores for proportion and intensity, then statistically analyzed as low (total score, 0–2) vs. high (total score, 3–8) expression.

Statistical analysis

All statistical analyses were performed using the SPSS 17.0 statistical software package (SPSS Inc., Chicago, IL, USA). The Fisher exact test or χ2 test was used to analyze the difference between two groups, while the hazard ratios and 95% confidence intervals were used to calculate the difference between low and high expression groups. Cumulative survival curves were generated using the Kaplan-Meier method and analyzed using a Cox regression test. Univariate and multivariate analyses were performed to analyze the association between clinicopathological parameters and patient outcomes. P<0.05 was considered to indicate a statistically significant difference between values.

Results

Expression of cathepsins B, D, G, K, L and V as well as RECK and VEGF in breast cancer tissue specimens

In the present study, the expression of cathepsins B, D, G, K, L and V was assessed using immunohistochemistry. In addition, cathepsin expression levels were compared with those of RECK, a metastasis suppressor with protease inhibitor-like domains, and VEGF, which is involved in the proliferation and metastasis of cancer cells. As shown in Fig. 1, all members of these cathepsin families as well as RECK and VEGF demonstrated positive cytoplasmic staining in these breast cancer tissues. Of note, cathepsin B was expressed in 109/142 (76.76%), cathepsin D in 91/155 (58.71%), cathepsin G in 99/171 (57.89%), cathepsin K in 97/143 (67.83%), cathepsin L in 95/166 (57.23%), cathepsin V in 45/164 (27.44%), RECK in 67/175 (38.29%) and VEGF in 100/164 (60.98%) samples of breast cancer tissues. Due to unsuccessful staining in certain samples, staining information could not be obtained from the total 188 samples.

Associations between cathepsins B, D, G, K, L and V as well as RECK and VEGF expression in breast cancer tissue specimens

The expression of certain proteins may have an effect on the expression of other proteins in the same family. In order to determine whether cathepsins interact to effect each others expression, the dependence in expression of different members of the cathepsin family, as well as RECK and VEGF, was analyzed. The results revealed that the expression of cathepsin B was associated with the expression of cathepsins D (P=0.036) and L (P=0.002), while cathepsin D expression was associated with the expression of cathepsins G (P=0.016), L (P=0.003) and V (P=0.006) (Table I). In addition, cathepsin G expression was associated with the expression of cathepsins K (P=0.023), L (P=0.035) and V (P=0.025) (Table I). Furthermore, cathepsin L expression was associated with that of VEGF (P=0.032), while VEGF expression was associated with RECK expression (P=0.001) (Table I).

Table I.

Association of these protein expressions in breast cancer tissues.

Table I.

Association of these protein expressions in breast cancer tissues.

Cathepsin DCathepsin GCathepsin KCathepsin LCathepsin VVEGFRECK







VariableLHPLHPLHPLHPLHPLHPLHP
Cathepsin B
  −55  80.03649170.10536160.83052140.00242180.43930380.10043290.625
  +4116 3925 3715 3329 4815 1740 3528
Cathepsin D
  −89280.01667260.96982300.00385240.00645680.15280370.248
  +1815 21  8 1518 1715 823 1814
Cathepsin G
  −75210.02381300.03584250.02541690.92578310.073
  +2115 2520 2618 1626 2221
Cathepsin K
  −68260.12469230.74736550.18066330.259
  +2115 2610 1027 2217
Cathepsin L
  −78270.29244580.03272370.111
  +3116 1236 2724
Cathepsin V
  −45620.05970450.673
  +1132 2418
VEGF
  −47120.001
  +5446

[i] L, low expression; H, high expression; VEGF, vascular endothelial growth factor; RECK, reversion-inducing cysteine-rich protein with Kazal motifs.

Association of cathepsins B, D, G, K, L and V as well as RECK and VEGF expression with clinicopathological parameters

The expression of cathepsins B, D, G, K, L and V as well as RECK and VEGF were subsequently evaluated for their associations with the clinicopathological parameters of breast cancer patients. The results demonstrated that cathepsin L expression was associated with advanced tumor stage, while the expression of cathepsins B (P=0.033) and K (P=0.038) was associated with ER expression (P=0.022) (Table II). In addition, cathepsin K expression was found to be associated with PR expression (P=0.022) and it was revealed that RECK expression was associated with ErbB2 expression (P=0.023) as well as lymph node metastasis (P=0.023) (Table II). Furthermore, cathepsin V expression was associated with distant metastasis (P=0.035), while cathepsin D expression was associated with breast cancer metastasis to the chest (P=0.041) (Table II). However, there was no association identified between protein expression and patient age, tumor size, histological grade, menopausal status, bone metastasis, lung metastasis, hepatic metastasis, brain metastasis or opposite breast metastasis (Table II).

Table II.

Association of cathepsins B, D, C, K, L and V as well as RECK and VEGF expression with clinicopathological parameters from breast cancer patients.

Table II.

Association of cathepsins B, D, C, K, L and V as well as RECK and VEGF expression with clinicopathological parameters from breast cancer patients.

Cathepsin BCathepsin DCathepsin GCathepsin KCathepsin LCathepsin VRECKVEGF








CharacteristicLowHighLowHighLowHighLowHighLowHighLowHighLowHighLowHigh
Age
  <504137  6621  6826  5919  6031  63316235  3359
  >503628  5612  5521  4421  5520  55154631  2944
  P-value 0.661 0.327 0.997 0.292 0.304 0.103 0.573 0.611
Tumor size
  <2.0 cm2114  265  2512  267  336  24121226  1918
  2.0–5.0 cm4240  7622  7927  5627  6636  75243860  7138
  >5.0 cm1411  206  198  216  179  19101217  1811
  P-value 0.670 0.733 0.695 0.359 0.075 0.406 0.663 0.298
Histological grade
  Grade 11819  3110  3212  267  3213  28153312  1827
  Grade 24638  7118  6929  5830  6630  68255546  3361
  Grade 3138  205  226  193  178  226208  1115
  P-value 0.615 0.852 0.694 0.099 0.950 0.435 0.051 0.739
Tumor stage
  0/I116  141  154  143  180  126  712     99
  IIA/IIB4241  7223  7729  5923  6139  69303564  6937
  III/IV2316  338  2913  2813  3212  34102025  2719
  P-value 0.464 0.289 0.723 0.553 0.004 0.582 0.578 0.420
ER
  −2914  439  4413  398  3515  42104017  2428
  +4751  7824  7834  6332  7936  75366848  3775
  P-value 0.033 0.374 0.300 0.038 0.868 0.081 0.140 0.106
PR
  −2217  468  4515  449  3617  43134118  2331
  +5448  7525  7732  5831  7834  74336747  3872
  P-value 0.712 0.142 0.545 0.022 0.824 0.304 0.168 0.316
ErbB2
  −1521  3511  3714  3113  3721  34143712  2127
  +6143  8621  8433  7227  7639  82327053  4075
  P-value 0.078 0.550 0.920 0.835 0.233 0.888 0.023 0.281
Lymph node
  Negative3525  4913  5815  4414  5019  46243935  2445
  Positive3939  7020  6331  5526  6231  70216729  3656
  P-value 0.330 0.854 0.074 0.307 0.430 0.116 0.023 0.572
Menopausal status
  Pre-menopausal4340  6723  7427  6121  6334  66336636  3363
  Post-menopausal3325  5510  4920  4219  5217  52134130  2939
  P-value 0.551 0.127 0.747 0.466 0.152 0.063 0.354   0.282
Distant metastasis
  −5639  7123  7928  5825  7333  69353968  6942
  +2126  5110  4419  4515  4218  49112335  3924
  P-value 0.108 0.230 0.574 0.501 0.829 0.035 0.685  0.973
Bone metastasis
  −6250  9427  9637  7532  8744  89395082  8850
  +1515  286  2710  288  287  2971221  2016
  P-value 0.601 0.557 0.924 0.374 0.122 0.193 0.872 0.366
Lung metastasis
  −6952  992810339  8234  9742  95415189  9154
  +  813  235  208  216  189  2351114  1712
  P-value 0.108 0.624 0.905 0.460 0.748 0.817 0.472 0.675
Hepatic metastasis
  −71551063110942  88361044510343579110056
  +  610  162  145  154  116  153  512     810
  P-value 0.154 0.262 0.891 0.471 0.666 0.255 0.463 0.104
Brain metastasis
  −776512033120471004011351116466210110964
  +  10     20     30     30     20     20  02     02
  P-value 0.357 0.459 0.280 0.275 0.343 0.374 0.270 0.069
Chest metastasis
  −745810814111144  913710448107435694  9861
  +  37  140  123  123  113  113  69  105
  P-value 0.111 0.041 0.488 0.467 0.431 0.564 0.839  0.701
Opposite breast
  −77631173211945  99391114911346609910365
  +  02     51     42     41     42     501  24     51
  P-value 0.121 0.778 0.751 0.686 0.888 0.156 0.827   0.275

[i] VEGF, vascular endothelial growth factor; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; ER, estrogen receptor; PR, progesterone receptor; ErbB2, erythroblastic leukemia viral oncogene homolog 2.

Association of cathepsins B, D, G, K, L and V as well as RECK and VEGF expression with the prognosis of breast cancer patients

Associations of the expression of cathepsins B, D, G, K, L and V as well as RECK and VEGF proteins with breast cancer patient prognosis were determined. The results revealed that high expression levels of cathepsin D and B and VEGF were associated with poor disease-free survival in breast cancer patients (Fig. 2). However, the expression of other proteins did not show any association with disease-free survival of these patients (data not shown).

Furthermore, univariate analysis data indicated that breast cancer metastasis to the bone and the expression of cathepsin B proteins were associated with poor disease-free survival. In addition, multivariate analysis demonstrated that PR expression was associated with poor disease-free survival and cathepsin B expression was only marginally associated with poor disease-free survival (P=0.058) (Table III).

Table III.

Cox regression analysis of disease-free survival according to clinicopathological parameters and protein expression.

Table III.

Cox regression analysis of disease-free survival according to clinicopathological parameters and protein expression.

Univariate analysisMultivariate analysis


Exp (B)95% CIP-valueExp (B)95% CIP-value
pTNM1.4960.939–2.3840.0901.6520.816–3.3410.163
Bone metastasis1.7801.067–2.9700.0272.0690.930–4.6060.75
Cathepsin B0.2800.140–0.5610.0000.4710.216–1.0260.058
ER0.6250.370–1.0550.0780.6130.246–1.5290.294
PR0.6410.384–1.0700.0890.4700.224–0.9850.046
Cathepsin D0.4610.205–1.0350.0610.7700.187–3.1650.717
VEGF0.5800.338–0.9950.0480.4290.209–0.8820.021

[i] Exp (B), relative risk ratio; CI, confidence interval; pTNM, pathological tumor-node-metastasis; ER, estrogen receptor; PR, progesterone receptor; VEGF, vascular endothelial growth factor.

Discussion

The development of breast cancer involves a progressive multistage process, from premalignant lesion, to ductal carcinoma in situ, to invasive carcinoma and then to metastatic disease (19). Given the variability in clinical progression and its high incidence and mortality rates, the identification of biomarkers that are able to predict tumor behavior may be particularly important in breast cancer (19). Therefore, the current study aimed to detected the expression of different cathepsins as well as RECK and VEGF proteins in breast cancer tissue specimens. The results demonstrated that cathepsin B was expressed in 109/142 (76.76%), cathepsin D in 91/155 (58.71%), cathepsin G in 99/171 (57.89%), cathepsin K in 97/143 (67.83%), cathepsin L in 95/166 (57.23%), cathepsin V in 45/164 (27.44%), RECK in 67/175 (38.29%) and VEGF in 100/164 (60.98%) samples of breast cancer tissues. It was also determined that the expression of cathepsin L was associated with advanced tumor stage, the expression of cathepsins B and K was associated with positive ER expression and that of cathepsin K was associated with PR expression. In addition, the expression of cathepsins V and D was associated with breast cancer metastasis. Furthermore, the expression of cathepsins B and D as well as that of VEGF was associated with poor disease-free survival in breast cancer patients. Univariate analysis revealed that breast cancer metastasis to the bone as well as the expression of cathepsin B and VEGF proteins were associated with poor disease-free survival. In addition, multivariate analysis demonstrated that PR and VEGF expression were significantly associated with poor disease-free survival of the patients, while cathepsin B expression was only marginally associated with poor disease-free survival. Therefore, the present results indicated that targeting cathepsin B and D may have a potential therapeutic benefit for breast cancer patients.

Cathepsins are a superfamily of proteins that are highly expressed in various types of human cancers and have been associated with cancer metastasis (6). Each cathepsin member has relatively different functions and thus, has a different role under normal as well as disease conditions. In cancer, cathepsins have been reported to have various functions, including the regulation of tissue remodeling, cell proliferation and angiogenesis, as well as cancer progression and metastasis (6). Several members of the cathepsin family have previously been studied in breast cancer (31). The results of the present study indicated that the expression of cathepsin V was associated with distant breast cancer metastasis and expression of cathepsin D was associated with breast cancer metastasis to the chest. These results were consistent with those of previously published studies suggesting that members of the cathepsin family were highly expressed in metastatic tumors (10,11,14,19). Cathepsin D protein has been reported to be overexpressed in breast cancer and hyper-secreted by epithelial breast cancer cells (21,32,33). Other previous studies have suggested that cathepsin D expression may be an independent predictor for poor prognosis of breast cancer patients as cathepsin D expression was associated with a high incidence of cancer metastasis (20,34). Consistent with these previous findings, the current study also demonstrated that high expression of cathepsin D protein was associated with poor prognosis of breast cancer patients; however, multivariate analysis failed to indicate that this was an independent predictor of disease-free survival. In addition, numerous studies have suggested that cathepsin B overexpression was associated with the invasive and metastatic phenotypes of various cancers (15,35). However, the role of cathepsin B in breast cancer remains to be fully elucidated (23,36). In the current study, expression of cathepsin B showed a trend (P=0.058) to independently predict breast cancer disease-free survival; however, this results was not statistically significant. Thus, further studies are required with a larger sample size in order to verify the role of cathepsins in breast cancer and their potential use as biomarkers for disease progression.

Numerous previous efforts have been made to develop specific inhibitors to target the activity of each cathepsin family member (26,37,38). For example, intraperitoneal administration of a highly selective cathepsin B inhibitor, such as CA-074, was reported to reduce the metastatic potential of breast cancer cells in nude mice (39). In addition, inhibitors of the other cysteine cathepsins, including S, L, C and K, are also available (40).

In conclusion, the present study demonstrated that the altered expression of cathepsins, in particular cathepsins B and D, was associated with breast cancer progression and poor disease-free survival. However, future studies are required in order to investigate whether the targeting of these two cathepsins, B and D, may have potential therapeutic use for attenuating the progression of breast cancer.

Acknowledgements

This study was supported by the Cooperation Project of China and Slovenia (grant no. 10–15 to Tao Sun).

Glossary

Abbreviations

Abbreviations:

ER

estrogen receptor

PR

progesterone-receptor

RECK

reversion-inducing cysteine-rich protein with Kazal motifs

VEGF

vascular endothelial growth factor

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January-2016
Volume 11 Issue 1

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Online ISSN:1792-1082

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Copy and paste a formatted citation
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Spandidos Publications style
Sun T, Jiang D, Zhang L, Su Q, Mao W and Jiang C: Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients. Oncol Lett 11: 575-583, 2016.
APA
Sun, T., Jiang, D., Zhang, L., Su, Q., Mao, W., & Jiang, C. (2016). Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients. Oncology Letters, 11, 575-583. https://doi.org/10.3892/ol.2015.3960
MLA
Sun, T., Jiang, D., Zhang, L., Su, Q., Mao, W., Jiang, C."Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients". Oncology Letters 11.1 (2016): 575-583.
Chicago
Sun, T., Jiang, D., Zhang, L., Su, Q., Mao, W., Jiang, C."Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients". Oncology Letters 11, no. 1 (2016): 575-583. https://doi.org/10.3892/ol.2015.3960