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Published in: Breast Cancer Research 3/2003

Open Access 01-06-2003 | Research article

Detection of hepatocyte growth factor/scatter factor receptor (c-Met) in axillary drainage after operations for breast cancer using reverse transcriptase–polymerase chain reaction

Authors: Ron Greenberg, Ignat Schwartz, Yehuda Skornick, Ofer Kaplan

Published in: Breast Cancer Research | Issue 3/2003

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Abstract

Background

The diverse biological effects of hepatocyte growth factor/scatter factor (HGF/SF) are mediated by c-Met, which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with the development and progression of malignant processes. In this study we examined whether Met can be detected in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance.

Methods

Thirty-one consecutive patients with invasive ductal carcinoma of the breast suitable for breast-conserving treatment were studied. The output of the drain that had been placed in the axilla during the operation was collected, and the presence of Met and β-actin were assessed by reverse transcriptase–polymerase chain reaction (RT–PCR) assays. The data were compared with the pathological features of the tumor and the axillary lymph nodes, and with the estrogen receptor and progesterone receptor status.

Results

RT–PCR of the axillary lymphatic drainage was positive for Met in 23 (74.2%) of the patients. Positive assays were correlated with increasing tumor size and grade, with capillary and lymphatic invasion, and with lymph node metastasis (P < 0.02, for all comparisons). All 12 patients with axillary lymph node metastases had positive assays for Met, compared with 57.9% of patients without lymph node metastases. All five patients with tumor involvement in the margins of the resection had positive assays for Met in their lymphatic fluid, compared with 18 of 26 positive assays (69.2%) for patients without involved margins (P < 0.04). Finally, Met showed negative correlations with positivity for estrogen receptor and progesterone receptor (P < 0.02).

Conclusion

Met can be detected in the axillary fluids of patients with breast cancer and its expression in the axillary drainage may have potential as a prognostic factor. This finding might be relevant to therapeutic considerations, because a positive assay for Met in histologically node-negative patients might point to the need to search for node microinvasion or involvement of the excision margins with tumor.
Literature
1.
go back to reference Berois N, Varangot M, Aizen B, Estrugo R, Zarantonelli L, Fernandez P, Krygler G, Simonet F, Barrios E, Muse I, Osinaga E: Molecular detection of cancer cells in bone marrow and peripheral blood of patients with operable breast cancer. Comparison of CK19, MUC1 and CEA using RT–PCR. Eur J Cancer. 2000, 36: 717-723. 10.1016/S0959-8049(99)00338-X.CrossRefPubMed Berois N, Varangot M, Aizen B, Estrugo R, Zarantonelli L, Fernandez P, Krygler G, Simonet F, Barrios E, Muse I, Osinaga E: Molecular detection of cancer cells in bone marrow and peripheral blood of patients with operable breast cancer. Comparison of CK19, MUC1 and CEA using RT–PCR. Eur J Cancer. 2000, 36: 717-723. 10.1016/S0959-8049(99)00338-X.CrossRefPubMed
2.
go back to reference Yeu-Tsu ML: Patterns of metastasis and natural courses of breast carcinoma. Cancer. 1994, 74: 2403-2413.CrossRef Yeu-Tsu ML: Patterns of metastasis and natural courses of breast carcinoma. Cancer. 1994, 74: 2403-2413.CrossRef
3.
go back to reference Hellman S: Natural history of small breast cancers. J Clin Oncol. 1994, 12: 2229-2234.PubMed Hellman S: Natural history of small breast cancers. J Clin Oncol. 1994, 12: 2229-2234.PubMed
4.
go back to reference International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet. 1990, 335: 1565-1568. 10.1016/0140-6736(90)91386-O. International (Ludwig) Breast Cancer Study Group: Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet. 1990, 335: 1565-1568. 10.1016/0140-6736(90)91386-O.
5.
go back to reference Frank JA, Ling A, Patronas NJ: Detection of malignant bone tumors: MR imaging vs scintigraphy. Am J Roentgenol. 1990, 55: 1043-1048.CrossRef Frank JA, Ling A, Patronas NJ: Detection of malignant bone tumors: MR imaging vs scintigraphy. Am J Roentgenol. 1990, 55: 1043-1048.CrossRef
6.
go back to reference Molino A, Colombatti M, Bonetti F, Zarrdini M, Pasini F, Perini A, Pelosi G, Tridente G, Veneri D, Cetto GL: A comparative analysis of three different techniques for the detection of breast cancer cell in bone marrow. Cancer. 1991, 67: 1033-1036.CrossRefPubMed Molino A, Colombatti M, Bonetti F, Zarrdini M, Pasini F, Perini A, Pelosi G, Tridente G, Veneri D, Cetto GL: A comparative analysis of three different techniques for the detection of breast cancer cell in bone marrow. Cancer. 1991, 67: 1033-1036.CrossRefPubMed
7.
go back to reference Mattano LA, Moss T, Emerson SG: Sensitive detection of rare circulating neuroblastoma cells by the reverse transcriptase–polymerase chain reaction. Cancer Res. 1992, 52: 4701-4705.PubMed Mattano LA, Moss T, Emerson SG: Sensitive detection of rare circulating neuroblastoma cells by the reverse transcriptase–polymerase chain reaction. Cancer Res. 1992, 52: 4701-4705.PubMed
8.
go back to reference Campana D, Pui CH: Detection of minimal residual disease in acute leukemias: methodological advances and clinical significance. Blood. 1995, 85: 1416-1434.PubMed Campana D, Pui CH: Detection of minimal residual disease in acute leukemias: methodological advances and clinical significance. Blood. 1995, 85: 1416-1434.PubMed
9.
go back to reference Keene SA, Demeure MJ: The clinical significance of micro metastases and molecular metastases. Surgery. 2001, 129: 1-5. 10.1067/msy.2001.117979.CrossRefPubMed Keene SA, Demeure MJ: The clinical significance of micro metastases and molecular metastases. Surgery. 2001, 129: 1-5. 10.1067/msy.2001.117979.CrossRefPubMed
10.
go back to reference Gusteron B, Ott R: Occult axillary lymph-node micrometastases in breast cancer. Lancet. 1990, 336: 434-435. 10.1016/0140-6736(90)91978-J.CrossRef Gusteron B, Ott R: Occult axillary lymph-node micrometastases in breast cancer. Lancet. 1990, 336: 434-435. 10.1016/0140-6736(90)91978-J.CrossRef
11.
go back to reference Schoenfeld A, Luqmani Y, Smith D: Detection of breast cancer micro metastases in axillary lymph nodes using polymerase chain reaction. Cancer Res. 1994, 54: 2986-2990.PubMed Schoenfeld A, Luqmani Y, Smith D: Detection of breast cancer micro metastases in axillary lymph nodes using polymerase chain reaction. Cancer Res. 1994, 54: 2986-2990.PubMed
12.
go back to reference Nishiyama T, Sasaki T, Takaishi K, Kato M, Yaku H, Araki K, Matsuura Y, Takai Y: rac p21 is involved in insulin-induced membrane ruffling and rho p21 is involved in hepatocyte growth factor- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced membrane ruffling in KB cells. Mol Cell Biol. 1994, 14: 2447-2456.CrossRefPubMedPubMedCentral Nishiyama T, Sasaki T, Takaishi K, Kato M, Yaku H, Araki K, Matsuura Y, Takai Y: rac p21 is involved in insulin-induced membrane ruffling and rho p21 is involved in hepatocyte growth factor- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced membrane ruffling in KB cells. Mol Cell Biol. 1994, 14: 2447-2456.CrossRefPubMedPubMedCentral
13.
go back to reference Ridley AJ, Comoglio PM, Hall A: Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol Cell Biol. 1995, 15: 1110-1122.CrossRefPubMedPubMedCentral Ridley AJ, Comoglio PM, Hall A: Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol Cell Biol. 1995, 15: 1110-1122.CrossRefPubMedPubMedCentral
14.
go back to reference Jeffers M, Rong S, Woude GF: Hepatocyte growth factor/scatter factor–Met signaling in tumorigenicity and invasion/metastasis. J Mol Med. 1996, 74: 505-513. 10.1007/s001090050053.CrossRefPubMed Jeffers M, Rong S, Woude GF: Hepatocyte growth factor/scatter factor–Met signaling in tumorigenicity and invasion/metastasis. J Mol Med. 1996, 74: 505-513. 10.1007/s001090050053.CrossRefPubMed
15.
go back to reference Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C: Essential role for the c-Met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995, 376: 768-771. 10.1038/376768a0.CrossRefPubMed Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C: Essential role for the c-Met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995, 376: 768-771. 10.1038/376768a0.CrossRefPubMed
16.
go back to reference Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C: Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995, 373: 699-702. 10.1038/373699a0.CrossRefPubMed Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C: Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995, 373: 699-702. 10.1038/373699a0.CrossRefPubMed
17.
go back to reference Giordano S, Zhen Z, Medico E, Gaudino G, Galimi F, Comoglio PM: Transfer of motogenic and invasive response to scatter factor/hepatocyte growth factor by transfection of human MET protooncogene. Proc Natl Acad Sci USA. 1993, 90: 649-653.CrossRefPubMedPubMedCentral Giordano S, Zhen Z, Medico E, Gaudino G, Galimi F, Comoglio PM: Transfer of motogenic and invasive response to scatter factor/hepatocyte growth factor by transfection of human MET protooncogene. Proc Natl Acad Sci USA. 1993, 90: 649-653.CrossRefPubMedPubMedCentral
18.
go back to reference Matsumoto K, Matsumoto K, Nakamura T, Kramer RH: Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. J Biol Chem. 1994, 269: 31807-31813.PubMed Matsumoto K, Matsumoto K, Nakamura T, Kramer RH: Hepatocyte growth factor/scatter factor induces tyrosine phosphorylation of focal adhesion kinase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells. J Biol Chem. 1994, 269: 31807-31813.PubMed
19.
go back to reference Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF: Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol Cell Biol. 1992, 12: 5152-5158.CrossRefPubMedPubMedCentral Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S, Vande Woude GF: Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol Cell Biol. 1992, 12: 5152-5158.CrossRefPubMedPubMedCentral
20.
go back to reference Rosen EM, Knesel J, Goldberg ID, Jin L, Bhargava M, Joseph A, Zitnik R, Wines J, Kelley M, Rockwell S: Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor. Int J Cancer. 1994, 57: 706-714.CrossRefPubMed Rosen EM, Knesel J, Goldberg ID, Jin L, Bhargava M, Joseph A, Zitnik R, Wines J, Kelley M, Rockwell S: Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor. Int J Cancer. 1994, 57: 706-714.CrossRefPubMed
21.
go back to reference Leake R, Barnes D, Pinder S, Ellis Y, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R: Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol. 2000, 53: 634-635. 10.1136/jcp.53.8.634.CrossRefPubMedPubMedCentral Leake R, Barnes D, Pinder S, Ellis Y, Anderson L, Anderson T, Adamson R, Rhodes T, Miller K, Walker R: Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol. 2000, 53: 634-635. 10.1136/jcp.53.8.634.CrossRefPubMedPubMedCentral
22.
go back to reference Parr C, Jiang WG: Expression of hepatocyte growth factor/ scatter factor, its activator, inhibitors and the c-Met receptor in human cancer cells. Int J Oncol. 2001, 19: 857-863.PubMed Parr C, Jiang WG: Expression of hepatocyte growth factor/ scatter factor, its activator, inhibitors and the c-Met receptor in human cancer cells. Int J Oncol. 2001, 19: 857-863.PubMed
23.
go back to reference Tomioka D, Maharani N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, Nakamura T: Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 2001, 61: 7518-7524.PubMed Tomioka D, Maharani N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, Nakamura T: Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res. 2001, 61: 7518-7524.PubMed
24.
go back to reference Kermorgant S, Aparicio T, Dessirier V, Lewin MJ, Lehy T: Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. Carcinogenesis. 2001, 22: 1035-1042. 10.1093/carcin/22.7.1035.CrossRefPubMed Kermorgant S, Aparicio T, Dessirier V, Lewin MJ, Lehy T: Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. Carcinogenesis. 2001, 22: 1035-1042. 10.1093/carcin/22.7.1035.CrossRefPubMed
25.
go back to reference Wang Y, Selden AC, Morgan N, Stamp GWH, Hodgson HJF: Hepatocyte growth factor/scatter factor expression in human mammary epithelium. Am J Pathol. 1994, 144: 675-681.PubMedPubMedCentral Wang Y, Selden AC, Morgan N, Stamp GWH, Hodgson HJF: Hepatocyte growth factor/scatter factor expression in human mammary epithelium. Am J Pathol. 1994, 144: 675-681.PubMedPubMedCentral
26.
go back to reference Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K, Park M, Goldberg ID, Rosen EM: Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer. 1997, 15: 749-761. 10.1002/(SICI)1097-0142(19970215)79:4<749::AID-CNCR12>3.0.CO;2-#.CrossRef Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K, Park M, Goldberg ID, Rosen EM: Expression of scatter factor and c-met receptor in benign and malignant breast tissue. Cancer. 1997, 15: 749-761. 10.1002/(SICI)1097-0142(19970215)79:4<749::AID-CNCR12>3.0.CO;2-#.CrossRef
27.
go back to reference Tuck AB, Park M, Sterns EE, Boag A, Elliott BE: Coexpression of hepatocyte growth factor and receptor met in human breast carcinoma. Am J Pathol. 1996, 148: 225-231.PubMedPubMedCentral Tuck AB, Park M, Sterns EE, Boag A, Elliott BE: Coexpression of hepatocyte growth factor and receptor met in human breast carcinoma. Am J Pathol. 1996, 148: 225-231.PubMedPubMedCentral
28.
go back to reference Elliott BE, Hung WL, Boag AH, Tuck AB: The role of hepatocyte growth factor (scatter factor) in epithelial mesencymal transition and breast cancer. Can J Physiol Pharmacol. 2002, 80: 91-102. 10.1139/y02-010.CrossRefPubMed Elliott BE, Hung WL, Boag AH, Tuck AB: The role of hepatocyte growth factor (scatter factor) in epithelial mesencymal transition and breast cancer. Can J Physiol Pharmacol. 2002, 80: 91-102. 10.1139/y02-010.CrossRefPubMed
29.
go back to reference Maemura M, Lino Y, Yokoe T, Horiguchi J, Takei H, Koibuchi Y, Horii Y, Takeyoshi I, Ohwada S, Morishita Y: Serum concentration of hepatocyte growth factor in patients with metastatic breast cancer. Cancer Lett. 1998, 24: 215-220. 10.1016/S0304-3835(98)00014-7.CrossRef Maemura M, Lino Y, Yokoe T, Horiguchi J, Takei H, Koibuchi Y, Horii Y, Takeyoshi I, Ohwada S, Morishita Y: Serum concentration of hepatocyte growth factor in patients with metastatic breast cancer. Cancer Lett. 1998, 24: 215-220. 10.1016/S0304-3835(98)00014-7.CrossRef
30.
go back to reference Yamashita JI, Ogawa M, Yamashita SI, Nomura K, Kuramoto M, Saishoji T, Shin S: Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res. 1994, 54: 1630-1633.PubMed Yamashita JI, Ogawa M, Yamashita SI, Nomura K, Kuramoto M, Saishoji T, Shin S: Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res. 1994, 54: 1630-1633.PubMed
31.
go back to reference Shimabukuro K, Ichinose S, Koike R, Kubota T, Yamaguchi M, Miyasaka M, Aso T: Hepatocyte growth factor/scatter factor is implicated in the mode of stromal invasion of uterine squamous cervical cancer. Gynecol Oncol. 2001, 83: 205-215. 10.1006/gyno.2001.6347.CrossRefPubMed Shimabukuro K, Ichinose S, Koike R, Kubota T, Yamaguchi M, Miyasaka M, Aso T: Hepatocyte growth factor/scatter factor is implicated in the mode of stromal invasion of uterine squamous cervical cancer. Gynecol Oncol. 2001, 83: 205-215. 10.1006/gyno.2001.6347.CrossRefPubMed
32.
go back to reference Tacchini L, Dansi P, Matteucci E, Desiderio MA: Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis. 2001, 22: 1363-1371. 10.1093/carcin/22.9.1363.CrossRefPubMed Tacchini L, Dansi P, Matteucci E, Desiderio MA: Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis. 2001, 22: 1363-1371. 10.1093/carcin/22.9.1363.CrossRefPubMed
33.
go back to reference Kermorgant S, Dessirier V, Lewin MJ, Lehy T: HGF upregulates and modifies subcellular distribution of proteins in colon cancer cell enterocytic differentiation. Am J Physiol Gastrointest Liver Physiol. 2001, 281: G1068-G1080.PubMed Kermorgant S, Dessirier V, Lewin MJ, Lehy T: HGF upregulates and modifies subcellular distribution of proteins in colon cancer cell enterocytic differentiation. Am J Physiol Gastrointest Liver Physiol. 2001, 281: G1068-G1080.PubMed
34.
go back to reference Marchetti A, Buttitta F, Bertacca G, Zavaglia K, Bevilacqua G, Angelucci D, Viacava P, Naccarato A, Bonadio A, Barassi F, Felicioni L, Salvatore S, Mucilli F: mRNA markers of breast cancer nodal metastases: compression between mammoglobin and carcinoembryonic antigen in 248 patients. J Pathol. 2001, 195: 186-190. 10.1002/path.943.CrossRefPubMed Marchetti A, Buttitta F, Bertacca G, Zavaglia K, Bevilacqua G, Angelucci D, Viacava P, Naccarato A, Bonadio A, Barassi F, Felicioni L, Salvatore S, Mucilli F: mRNA markers of breast cancer nodal metastases: compression between mammoglobin and carcinoembryonic antigen in 248 patients. J Pathol. 2001, 195: 186-190. 10.1002/path.943.CrossRefPubMed
35.
go back to reference Yuan Rq RQ, Fan S, Achary M, Stewart DM, Goldberg ID, Rosen EM: Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage. Cancer Res. 2001, 61: 8022-8031. Yuan Rq RQ, Fan S, Achary M, Stewart DM, Goldberg ID, Rosen EM: Altered gene expression pattern in cultured human breast cancer cells treated with hepatocyte growth factor/scatter factor in the setting of DNA damage. Cancer Res. 2001, 61: 8022-8031.
36.
go back to reference Skibinski G, Skibinska A, James K: Hepatocyte growth factor (HGF) protects c-met-expressing Burkitt's lymphoma cell lines from apoptotic death induced by DNA damaging agents. Eur J Cancer. 2001, 37: 1562-1569. 10.1016/S0959-8049(01)00164-2.CrossRefPubMed Skibinski G, Skibinska A, James K: Hepatocyte growth factor (HGF) protects c-met-expressing Burkitt's lymphoma cell lines from apoptotic death induced by DNA damaging agents. Eur J Cancer. 2001, 37: 1562-1569. 10.1016/S0959-8049(01)00164-2.CrossRefPubMed
Metadata
Title
Detection of hepatocyte growth factor/scatter factor receptor (c-Met) in axillary drainage after operations for breast cancer using reverse transcriptase–polymerase chain reaction
Authors
Ron Greenberg
Ignat Schwartz
Yehuda Skornick
Ofer Kaplan
Publication date
01-06-2003
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2003
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr588

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