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Original Article |

Serum Levels of Transforming Growth Factor β1 in Patients With Breast Cancer FREE

Shyr-Ming Sheen-Chen, MD; Han-Shiang Chen, MD; Chih-Wei Sheen; Hock-Liew Eng, MD; Wei-Jen Chen, MD, MS
[+] Author Affiliations

From the Division of General Surgery, Departments of Surgery (Dr Sheen-Chen), Colorectal Surgery (Dr H.-S. Chen), and Pathology (Ms Sheen and Drs Eng and W.-J. Chen), Chang Gung Memorial Hospital, Kaohsiung; College of Medicine, Chang Gung University, Linkou, Taiwan.


Arch Surg. 2001;136(8):937-940. doi:10.1001/archsurg.136.8.937.
Text Size: A A A
Published online

Hypothesis  Transforming growth factor β1 (TGF-β1) may be related to breast cancer progression.

Design  Prospective study.

Setting  University hospital.

Patients  Sixty consecutive patients with invasive breast cancer undergoing surgery were prospectively included and evaluated. The control group consisted of 14 patients with benign breast tumors (7 with fibrocystic disease and 7 with fibroadenoma).

Intervention  Venous blood samples were collected before the surgery. Sera were obtained by centrifugation and stored at –70°C until assayed. Serum concentrations of TGF-β1 were measured by quantitative sandwich enzyme immunoassay. Data on primary tumor stage, age, estrogen receptor status, lymph node status, distant metastases, and TNM staging (according to the Union Internationale Contre le Cancer) were reviewed and recorded.

Main Outcome Measures  Measurements of preoperative serum TGF-β1 levels in patients with breast cancer.

Results  The mean ± SD value of serum TGF-β1 in patients with invasive breast cancer was 498.7 ± 249.7 pg/mL and in the control group was 495.2 ± 225.5 pg/mL (P = .96). However, there were significantly higher serum levels of TGF-β1 in patients with more advanced lymph node status (P = .04), more advanced TNM stage (P = .005), and poorer histological grade (P = .02). In multivariate analysis, TNM staging (P = .02) was demonstrated to be the independent factor related to significantly higher serum levels of TGF-β1.

Conclusions  Patients with more advanced TNM stages were shown to have higher serum TGF-β1 levels. Thus, serum TGF-β1 levels may reflect the severity of invasive breast cancer.

MANY GROWTH factors and their receptors have been reported to play an important role in the growth regulation of breast cancer.1,2 One of these is transforming growth factor β (TGF-β).2,3 The TGF-β superfamily contains proteins that serve a wide variety of biological activities, including growth control, cellular differentiation, embryologic morphology, and immunity.4 Transforming growth factor β1 is the predominant form found in humans and is widely expressed in a variety of normal cells and organs. It is a multifunctional polypeptide, promoting angiogenesis, accumulation of extracellular matrix glycoproteins, and cell adhesion proteins, while inhibiting growth of both epithelial and immune cells.4 Transforming growth factor β1 has been reported to be overexpressed in many tumors including those of the breast and is thought to be related to tumor transformation and progression.58 Nevertheless, there are conflicting reports about the role of the expression of TGF-β1 in breast cancer.912 Thus, this study was designed with the aim to elucidate the possible relationship between TGF-β1 and breast cancer.

From November 1998 to February 2000, 60 consecutive patients with invasive breast cancer were included in the study. Venous blood samples were collected before surgery. Serum samples were obtained by centrifugation and stored at –70°C until assayed. All 60 patients were women aged between 32 and 79 years (mean, 50.3 years). Except for those with distant metastases, all patients underwent modified radical mastectomy, and the diagnosis of breast cancer was confirmed by histological examination. Invasive breast cancer was defined as carcinoma, regardless of origin (duct or lobule), with invasion to or beyond the basement membrane.13 Tumors were graded according to the criteria described by Bloom and Richardson.14 Primary tumor stage, age, estrogen receptor status, lymph node status, distant metastases, and TNM stage were recorded for all patients. Each patient was assessed preoperatively by a thorough physical examination, chest radiography, level of serum alkaline phosphatase, and mammogram. Bone scan and abdominal ultrasonography were performed for all patients with provisional clinical stage III disease to rule out the presence of distant metastases. Regardless of the provisional clinical stage, all patients with elevated serum alkaline phosphatase, special complaints such as bone pain, or any specific findings indicating the possibility of distant metastases such as hepatomegaly also underwent bone scan and abdominal ultrsonography to detect possible distant metastases. Estrogen receptor status was determined by immunohistochemical staining.1517 Fourteen patients with benign breast tumor (7 with fibrocystic disease and 7 with fibroadenoma) were used as the control group.

MEASUREMENT OF TGF-β1

An enzyme-linked immunosorbent assay kit was used for the quantitative determinations of serum TGF-β1 concentration. In brief, each serum sample was diluted and added to the microtiter wells precoated by TGF-β soluble receptor type II, followed by an additional incubation with an enzyme-linked polyclonal antibody specific for TGF-β1. Color development was performed using a tetramethyl benzidine–hydrogen dioxide mixture and terminated with sulfuric acid. The absorbance of each well was determined using a spectrophotometer.

STATISTICAL ANALYSIS

An independent sample t test and analysis of variance were used to compare the serum TGF-β1 levels between subgroups of the clinicopathologic variables as the univariate analysis. Multivariate analysis was performed using the linear regression stepwise method to compare the serum TGF-β1 levels in patients with breast cancer. A P value of less than .05 was considered statistically significant.

The mean ± SD value of serum TGF-β1 was 498.7 ± 249.7 pg/mL in patients with invasive breast cancer and 495.2 ± 225.5 pg/mL in the control group (P = .96). However, with the stratification of the above-mentioned clinicopathologic variables, patients with more advanced lymph node status (P = .04), more advanced TNM stage (P = .005), and poorer histological grade (P = .02) were shown to have significantly higher serum levels of TGF-β1 (Table 1). In multivariate analysis, TNM staging (P = .02) was demonstrated to be the independent factor related to significantly higher serum levels of TGF-β1 (Table 2).

Table Graphic Jump LocationTable 1. Serum Levels of TGF-β1 in Relation to Clinicopathologic Variables*
Table Graphic Jump LocationTable 2. Multivariate Analysis of Serum TGF-β1 Level in Patients With Breast Cancer*

The evaluation of the possible outcome of patients with breast cancer is important for planning treatment. Because no single prognostic factor can determine the status of a patient with breast cancer, physicians must consider all available prognostic data.1520 Angiogenesis is essential for tumor growth and metastasis and is regulated by numerous angiogenic factors. The recent study of Gunningham et al21 showed that the short form of the alternatively spliced flt-4—not its ligand, vascular endothelial growth factor C—is related to lymph node metastasis in human breast cancer. The recent study of Pawlowski et al22 confirmed that the 4 members of the type 1 growth factor receptor gene family such as epidermal growth factor, c-erb-b2, c-erb-b3, and c-erb-b4 are prognosis markers of tumor aggressiveness in breast cancer. We conducted this study to investigate any correlation between serum TGF-β1 and the clinicopathologic variables and to elucidate the possible relationship between the TGF-β1 and breast cancer. We included patients with invasive breast cancer only since the clinical course of intraductal, noninvasive breast cancer is usually quite different.

Transforming growth factor β1 has been reported to be overexpressed in many tumors, including those of the breast, and is thought to be related to tumor transformation and progression.58 The following mechanisms have been suggested to be related to tumor transformation and progression: (1) TGF-β1 production by tumor cells can enhance tumor growth through promoting angiogenesis and evading immune surveillance23,24; (2) TGF-β1 can promote accumulation of extracellular matrix glycoproteins and cell adhesion proteins, which may enhance the metastatic potential of the tumor25; (3) in vitro studies have demonstrated that the induction of TGF-β1 secretion may increase the cellular motility and the production of protease, thus enhancing the invasive potential of fibrosarcoma26; and (4) in addition to elevated TGF-β1, some tumor cells with mutations in the type II TGF-β receptor gene leading to the absence of the cell surface type II TGF-β receptor may avoid the TGF-β–mediated growth inhibitory effect.27

There are conflicting reports about the role of the expression of TGF-β1 in breast cancer.912 Some authors9,10 have claimed that the immunohistochemical staining intensity for TGF-β1 is positively associated with the rate of disease progression. To the contrary, Auvinen et al12 found that immunohistochemical staining for the expression of TGF-β1 is related to favorable prognostic factors. Also, Murray et al11 found that patients with high levels of TGF-β1 messenger RNA (mRNA) expression have a longer disease-free interval. The diversity of results among different series may be owing to different antibodies used to detect the expression of TGF-β1. Moreover, TGF-β protein and TGF-β mRNA expressions may not always be comparable. Peton et al28 demonstrated that TGF-β proteins are frequently found in the same cells as TGF-β mRNA but occasionally differences exist in the location of cells where TGF-β protein or TGF-β mRNA expressions are found. Finally, although semiquantitative evaluation is sufficient to differentiate negative from positive reactions, it may not be accurate enough to evaluate the intermediate patterns of staining.

We used the quantitative sandwich enzyme immunoassay to measure serum concentrations of TGF-β1, and our preliminary results showed that patients with more advanced lymph node status (P = .04), more advanced TNM stage (P = .005), and poorer histologic grade (P = .02) have significantly higher serum levels of TGF-β1 (Table 1). In multivariate analysis, TNM staging (P = .02) was demonstrated to be the independent factor related to significantly higher serum levels of TGF-β1 (Table 2). Such findings are more similar to reports by Gorsch et al9 and Walker and Dearing10 and suggest that TGF-β1 is related to tumor transformation and progression. The choice of serum for a quantitative analysis in our study could possibly avoid the above-mentioned disadvantages of a semiquantitative analysis by immunohistochemical staining.

Based on our preliminary results, the preoperative level of serum TGF-β1 is closely related to a more advanced TNM stage. Thus, serum TGF-β1 levels may reflect the severity of invasive breast cancer. Although the preliminary results seem promising, the follow-up in this series is still short; longer follow-up is needed before a substantial conclusion can be achieved.

Corresponding author and reprints: Shyr-Ming Sheen-Chen, MD, Professor and Chief, Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung, 123 Ta-Pei Rd, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan (e-mail: smsheen@yahoo.com).

Gasparini  GBevilacqua  PPozza  F  et al.  Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer. Br J Cancer. 1992;66970- 976
Link to Article
Derynck  RJarret  JAChen  EY  et al.  Human transforming growth factor-β complementary DNA sequences and expression in normal and transformed cells. Nature. 1985;316701- 705
Link to Article
Burt  DW Evolutionary grouping of transforming growth factor-β superfamily. Biochem Biophys Res Commun. 1992;184590- 595
Link to Article
Blobe  GCSchiemann  WPLodish  HF Role of transforming growth factor-β in human disease. N Engl J Med. 2000;3421350- 1358
Link to Article
Tsushima  HKawata  STamura  S  et al.  High levels of transforming growth factor-β1 in patients with colorectal cancer: association with disease progression. Gastroenterology. 1996;110375- 382
Link to Article
Comerci  JTRunowicz  CDFlander  KC  et al.  Altered expression of transforming growth factor-β1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix. Cancer. 1996;771107- 1114
Link to Article
Eder  IEStenzl  AHobisch  A  et al.  Transforming growth factors-β1 and β2 in serum and urine from patients with bladder carcinoma. J Urol. 1996;156953- 957
Link to Article
Friess  HYamanaka  YBuchler  M  et al.  Enhanced expression of transforming growth factor-β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;1051846- 1856
Gorsch  SMMemoli  VAStukel  TA  et al.  Immunohistochemical staining for transforming growth factor-beta 1 associates with disease progression in human breast cancer. Cancer Res. 1992;526949- 6952
Walker  RADearing  SJ Transforming growth factor-beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur J Cancer. 1992;28641- 644
Link to Article
Murray  PABarrett-Lee  PTravers  M  et al.  The prognostic significance of transforming growth factors in human breast cancer. Br J Cancer. 1993;671408- 1412
Link to Article
Auvinen  PLipponen  PJohansson  RSyrjanen  K Prognostic significance of TGF-β1 and TGF-β2 expressions in female breast cancer. Anticancer Res. 1995;152627- 2632
Not Available, The World Health Organization histological typing of breast tumor—2nd edition Am J Clin Pathol. 1982;78808- 816
Bloom  HJGRichardson  WW Histological grading and prognosis in breast cancer. Br J Cancer. 1957;11359- 377
Link to Article
Sheen-Chen  SMChen  WJEng  HLChou  FF Serum concentration of tumor necrosis factor in patients with breast cancer. Breast Cancer Res Treat. 1997;43211- 215
Link to Article
Sheen-Chen  SMEng  HLChou  FFChen  WJ The prognostic significance of proliferating cell nuclear antigen in patients with lymph node-positive breast cancer. Arch Surg. 1997;132264- 267
Link to Article
Sheen-Chen  SMChen  WJEng  HLChou  FF Serum-soluble interleukin-2 receptor concentrations in patients with breast cancer: a preliminary report. Changgeng Yi Xue Za Zhi. 1998;21133- 138
Sheen-Chen  SMChou  FFEng  HLChen  WJ An evaluation of the prognostic significance of HLA-DR expression in axillary-node-negative breast cancer. Surgery. 1994;116510- 515
Sheen-Chen  SMEng  HLSheen  CWCheng  YFChou  FFChen  WJ Serum levels of circulating intercellular adhesion molecule-1 in patients with breast cancer. Anticancer Res. 1997;172823- 2826
Sheen-Chen  SMChen  WJEng  HL  et al.  Evaluation of the prognostic value of serum soluble CD44 in patients with breast cancer. Cancer Invest. 1999;17581- 585
Link to Article
Gunningham  SPCurrie  MJHan  C  et al.  The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res. 2000;64278- 4286
Pawlowski  VRevillion  FHebbar  M  et al.  Prognostic value of the type 1 growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000;64217- 4225
Roberts  ABThompson  NLHeine  U  et al.  Transforming growth factor-β: possible roles in carcinogenesis. Br J Cancer. 1988;57594- 600
Link to Article
Ueki  NNakazato  MOhkawa  T  et al.  Excessive production of transforming growth factor-β1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim Biophys Acta. 1992;1137189- 196
Link to Article
Massague  JCheifetz  SLaiho  M  et al.  Tansforming growth factor-β. Cancer Surv. 1992;1281- 103
Samuel  SKHurta  RARKondaiah  P  et al.  Autocrine induction of tumor protease production and invasion by a metallothionen-regulated TGF-β1. EMBO J. 1992;111599- 1605
Derynck  RGoeddel  DVUllrich  A  et al.  Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors. Cancer Res. 1987;47707- 712
Peton  RSaxena  BJones  M  et al.  Immunohistochemical localization of TGF-β1, TGF-β2 and TGF-β3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991;1151091- 1105
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Serum Levels of TGF-β1 in Relation to Clinicopathologic Variables*
Table Graphic Jump LocationTable 2. Multivariate Analysis of Serum TGF-β1 Level in Patients With Breast Cancer*

References

Gasparini  GBevilacqua  PPozza  F  et al.  Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer. Br J Cancer. 1992;66970- 976
Link to Article
Derynck  RJarret  JAChen  EY  et al.  Human transforming growth factor-β complementary DNA sequences and expression in normal and transformed cells. Nature. 1985;316701- 705
Link to Article
Burt  DW Evolutionary grouping of transforming growth factor-β superfamily. Biochem Biophys Res Commun. 1992;184590- 595
Link to Article
Blobe  GCSchiemann  WPLodish  HF Role of transforming growth factor-β in human disease. N Engl J Med. 2000;3421350- 1358
Link to Article
Tsushima  HKawata  STamura  S  et al.  High levels of transforming growth factor-β1 in patients with colorectal cancer: association with disease progression. Gastroenterology. 1996;110375- 382
Link to Article
Comerci  JTRunowicz  CDFlander  KC  et al.  Altered expression of transforming growth factor-β1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix. Cancer. 1996;771107- 1114
Link to Article
Eder  IEStenzl  AHobisch  A  et al.  Transforming growth factors-β1 and β2 in serum and urine from patients with bladder carcinoma. J Urol. 1996;156953- 957
Link to Article
Friess  HYamanaka  YBuchler  M  et al.  Enhanced expression of transforming growth factor-β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;1051846- 1856
Gorsch  SMMemoli  VAStukel  TA  et al.  Immunohistochemical staining for transforming growth factor-beta 1 associates with disease progression in human breast cancer. Cancer Res. 1992;526949- 6952
Walker  RADearing  SJ Transforming growth factor-beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur J Cancer. 1992;28641- 644
Link to Article
Murray  PABarrett-Lee  PTravers  M  et al.  The prognostic significance of transforming growth factors in human breast cancer. Br J Cancer. 1993;671408- 1412
Link to Article
Auvinen  PLipponen  PJohansson  RSyrjanen  K Prognostic significance of TGF-β1 and TGF-β2 expressions in female breast cancer. Anticancer Res. 1995;152627- 2632
Not Available, The World Health Organization histological typing of breast tumor—2nd edition Am J Clin Pathol. 1982;78808- 816
Bloom  HJGRichardson  WW Histological grading and prognosis in breast cancer. Br J Cancer. 1957;11359- 377
Link to Article
Sheen-Chen  SMChen  WJEng  HLChou  FF Serum concentration of tumor necrosis factor in patients with breast cancer. Breast Cancer Res Treat. 1997;43211- 215
Link to Article
Sheen-Chen  SMEng  HLChou  FFChen  WJ The prognostic significance of proliferating cell nuclear antigen in patients with lymph node-positive breast cancer. Arch Surg. 1997;132264- 267
Link to Article
Sheen-Chen  SMChen  WJEng  HLChou  FF Serum-soluble interleukin-2 receptor concentrations in patients with breast cancer: a preliminary report. Changgeng Yi Xue Za Zhi. 1998;21133- 138
Sheen-Chen  SMChou  FFEng  HLChen  WJ An evaluation of the prognostic significance of HLA-DR expression in axillary-node-negative breast cancer. Surgery. 1994;116510- 515
Sheen-Chen  SMEng  HLSheen  CWCheng  YFChou  FFChen  WJ Serum levels of circulating intercellular adhesion molecule-1 in patients with breast cancer. Anticancer Res. 1997;172823- 2826
Sheen-Chen  SMChen  WJEng  HL  et al.  Evaluation of the prognostic value of serum soluble CD44 in patients with breast cancer. Cancer Invest. 1999;17581- 585
Link to Article
Gunningham  SPCurrie  MJHan  C  et al.  The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res. 2000;64278- 4286
Pawlowski  VRevillion  FHebbar  M  et al.  Prognostic value of the type 1 growth factor receptors in a large series of human primary breast cancers quantified with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000;64217- 4225
Roberts  ABThompson  NLHeine  U  et al.  Transforming growth factor-β: possible roles in carcinogenesis. Br J Cancer. 1988;57594- 600
Link to Article
Ueki  NNakazato  MOhkawa  T  et al.  Excessive production of transforming growth factor-β1 can play an important role in the development of tumorigenesis by its action for angiogenesis: validity of neutralizing antibodies to block tumor growth. Biochim Biophys Acta. 1992;1137189- 196
Link to Article
Massague  JCheifetz  SLaiho  M  et al.  Tansforming growth factor-β. Cancer Surv. 1992;1281- 103
Samuel  SKHurta  RARKondaiah  P  et al.  Autocrine induction of tumor protease production and invasion by a metallothionen-regulated TGF-β1. EMBO J. 1992;111599- 1605
Derynck  RGoeddel  DVUllrich  A  et al.  Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors. Cancer Res. 1987;47707- 712
Peton  RSaxena  BJones  M  et al.  Immunohistochemical localization of TGF-β1, TGF-β2 and TGF-β3 in the mouse embryo: expression patterns suggest multiple roles during embryonic development. J Cell Biol. 1991;1151091- 1105
Link to Article

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