c-kit and SCF Expression in Normal and Tumor Breast Tissue
Tóm tắt
Several studies have shown a role of the tyrosine kinase receptor, c-kit, and its ligand, SCF, during organogenesis, normal cell development and growth of some tumor histotypes. In breast cancer, studies using different methodologies have shown conflicting results. In the present study we analyzed c-kit and SCF in 14 normal mammary epithelia samples, in 16 in situ and in 75 invasive breast cancers. The expression of c-kit and SCF protein was analyzed by immunohistochemistry and mRNA expression was evaluated by in situ hybridization and reverse-transcriptase polymerase chain reaction (RT-PCR). The different methodologies gave somewhat different results. Using immunohistochemistry and in situ hybridization, protein and mRNA expression of c-kit and SCF were high in normal mammary gland, significantly lower in in situ and almost completely undetectable in invasive breast cancer. Conversely, using RT-PCR, mRNA expression was observed in normal tissue and in all pathologic lesions of mammary gland, probably due to the high sensitivity of the methodology or to the positivity of elements other than tumor cells expressing the receptor and/or its ligand. These results suggest that the c-kit/SCF pathway plays an important role in the maintenance of normal growth of mammary epithelium and that the process of malignant transformation is accompanied by their progressive loss. Furthermore, we demonstrated that different results are attributable to different methodologies and that morphologic approaches are the most reliable for defining the cellular source of c-kit or SCF expression.
Tài liệu tham khảo
Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A: Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6: 3341–3351, 1987
Besmer P, Murphy JE, George PC, Qiu F, Bergold PJ, Lederman L, Snyder Jr HW, Brodeur D, Zuckerman EE, Hardy WD: A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320: 415–421, 1986
Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A: Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 52: 6139–6143, 1992
Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C: Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem 42: 1417–1425, 1994
Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K, March CJ, Park LS, Martin U, Mochizuchi DY, Boswell HS, Burgess GS, Cosman D, Lyman SD: Identification of a ligand for the c-kit proto-oncogene. Cell 63: 167–174, 1990
Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P: The hematopoietic growth factor KL is encoded by the SI locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63: 225–233, 1990
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC, Jacobsen FW, Langley KE, Smith KA, Takeishi T, Cattanach BM, Galli SJ, Suggs SV: Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63: 213–224, 1990
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279: 577–580, 1998
Nakahara M, Isozaki K, Hirota S, Miyagawa J, Hase-Sawada N, Taniguchi M, Nishida T, Kanayama S, Kitamura Y, Shinomura Y, Matsuzawa Y: A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors. Gastroenterology 115: 1090–1095, 1998
Andersson J, Sjogren H, Meis-Kindblom JM, Stenman G, Aman P, Kindblom LG: The complexity of kit gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors. Am J Pathol 160: 15–22, 2002
Lasota J, Wozniak A, Sarlomo-Rikala M, Rys J, Kordek R, Nassar A, Sobin LH, Miettinen M: Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. Am J Pathol 157: 1091–1095, 2000
Simak R, Capodieci P, Cohen DW, Fair WR, Scher H, Melamed J, Drobnjak M, Heston WD, Stix U, Steiner G, Cordon-Carlo C: Expression of c-kit and kit-ligand in benign and malignant prostatic tissues. Histol Histopathol 15: 365–374, 2000
Inoue M, Kyo S, Fujita M, Enomoto T, Kondoh G: Coexpression of the c-kit receptor and stem cell factor in gynecological tumors. Cancer Res 54: 3049–3053, 1994
Parrott JA, Kim G, Skinner MK: Expression and action of kit ligand/stem cell factor in normal human and bovine ovarian surface epithelium and ovarian cancer. Biol Reprod 62: 1600–1609, 2000
Tonary AM, Macdonald EA, Faught W, Senterman MK, Vanderhyden BC: Lack of expression of c-kit in ovarian cancer is associated with poor prognosis. Int J Cancer 89: 242–250, 2000
Stanulla M, Welte K, Hadam MR, Pietsch T: Coexpression of stem cell factor and its receptor c-kit in human malignant glioma cell lines. Acta Neuropathol 89: 158–165, 1995
Hamel W, Westphal M: The road less travelled: c-kit and stem cell factor. J Neurooncol 35: 327–333, 1997
Vitali R, Cesi V, Nicotra MR, McDowell HP, Donfrancesco A, Mannarino O, Natali PG, Raschella G, Dominici C: c-kit is preferentially expressed in MYCN-amplified neuroblastoma and its effect on cell proliferation is inhibited in vitro by STI-571. Int J Cancer 106: 147–152, 2003
Bokemeyer C, Kuczyk MA, Serth J, Hartmann JT, Schmoll HJ, Jonas U, Kanz L: Treatment of clinical stage I testicular cancer and a possible role for new biologic prognostic parameters. J Cancer Res Clin Oncol 122: 575–584, 1996
Tsuura Y, Hiraki H, Watanabe K, Igarashi S, Shimamura K, Fukuda T, Suzuki T, Scito T: Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in humans: immunohistochemical study on formalin-fixed, paraffin embedded tissues. Virchows Arch 424: 135–141, 1994
Hibi K, Takahashi T, Sekido Y, Ueda R, Hida T, Ariyoshi Y, Takagi H, Takahashi T: Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer. Oncogene 6: 2291–2296, 1991
Krystal GW, Hines SJ, Organ CP: Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res 56: 370–376, 1996
Pietsch T, Nicotra MR, Fraioli R, Wolf HK, Mottolese M, Natali PG: Expression of the c-kit receptor and its ligand scf in non-small-cell-lung-carcinomas. Int J Cancer 75: 171–175, 1998
Natali PG, Nicotra MR, Winkler AB, Cavaliere R, Bigotti A, Ullrich A: Progression of human cutaneous melanoma is associated with loss of expression of c-kit proto-oncogene receptor. Int J Cancer 9: 197–201, 1992
Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A: Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer 52: 713–717, 1992
Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, Seito T, Sugiura T, Ariyoshi, Takahashi T, Ueda R: Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 142: 339–346, 1993
Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, Ogawa M: Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer 73: 1233–1236, 1996
Tsuura Y, Suzuki T, Honma K, Sano M: Expression of c-kit protein in proliferative lesions of human breast: sexual difference and close association with phosphotyrosine status. J Cancer Res Clin Oncol 128: 239–246, 2002
Natali PG, Berlingieri MT, Nicotra MR, Fusco A, Santoro E, Bigotti A, Vecchio G: Transformation of thyroid epithelium is associated with loss of c-kit receptor. Cancer Res 55: 1787–1791, 1995
Hines SJ, Organ C, Kornstein MJ, Krystal GW: Coexpression of the c-kit and stem cell factor genes in breast carcinoma. Cell Growth Differ 6: 769–779, 1995
Nishida K, Tsukamoto T, Uchida K, Takahashi T, Takahashi T, Ueda R: Introduction of the c-kit gene leads to growth suppression of a breast cancer cell line, MCF-7. Anticancer Res 16: 3397–3402, 1996
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M: Loss of AP-2 results in downregulation of c-kit and enhancement of melanoma tumorigenicity and metastasis. EMBO J 17: 4358–4369, 1998
Baldi A, Santini D, Battista T, Dragonetti E, Ferranti G, Petitti T, Groeger AM, Angelini A, Rossiello R, Baldi F, Natali PG, Paggi MG: Expression of AP-2 transcription factor and of its downstream target genes c-kit, E-cadherin and p21 in human cutaneous melanoma. J Cell Biochem 83: 364–372, 2001
Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH, Mueller SC: The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature 406: 742–747, 2000
De Paola F, Vecci AM, Granato AM, Liverani M, Monti F, Innoceta AM, Gianni L, Saragoni L, Ricci M, Falcini F, Amadori D, Volpi A: p27/kip I expression in normal epithelium, benign and neoplastic breast lesions. J Pathol 196: 26–31, 2002