Abstract
The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could affect tumor growth and survival thereby influencing both tumor aggressiveness and potential response to treatments. We have previously identified the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a differentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly differentiated tumors and higher stage. There was a significantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Burger AM, Zhang X, Li H, Ostrowski JL, Beatty B, Venanzoni M, Papas T, Seth A . 1998 Oncogene 16: 2459–2467
Degeorges A, Wang F, Frierson HF, Seth A, Chung LKW, Sikes RA . 1999 Cancer Res. 50: 2787–2790
Ellis MJ, Jenkins S, Hanfelt J, Redington ME, Taylor M, Leek R, Siddle K, Harris A . 1998 Breast Cancer Res. Treat. 52: 175–184
Kato MV, Sato H, Tsukada T, Ikawa Y, Aizawa S, Nagayoshi MA . 1996 Oncogene 12: 1361–1364
Komatsu S, Okazaki Y, Tateno M, Kawai J, Konno H, Kusakabe M, Yoshiki A, Muramatsu M, Held WA, Hayashizaki Y . 2000 Biochem. Biophys. Res. Commun. 267: 109–117
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP . 1998 Nat. Med. 4: 844–847
Landberg G, Roos G . 1997 APMIS 105: 575–589
Lodén M, Nielsen NH, Roos G, Emdin SO, Landberg G . 1999 Oncogene 22: 2557–2566
Lukas J, Aagaard L, Strauss M, Bartek K . 1995 Cancer Res. 55: 4818–4823
Martin JL, Baxter RCJ . 1999 Biol. Chem. 4: 16407–16411
Moch H, Schraml P, Bubendorf L, Mirlacher M, Kononen J, Gasser T, Mihatsch MJ, Kallioniemi OP, Sauter G . 1999 Am. J. Pathol. 154: 981–986
Nielsen NH, Arnerlov C, Emdin SO, Landberg G . 1996 Br. J. Cancer. 74: 874–880
Nielsen NH, Emdin SO, Cajander J, Landberg G . 1997 Oncogene 14: 295–304
Nielsen NH, Arnerlov C, Cajander S, Landberg G . 1998 Anal. Cell. Pathol. 17: 177–188
Nielsen NH, Lodén M, Cajander J, Emdin SO, Landberg G . 1999 Breast Cancer Res. Treat. 56: 105–112
Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M . 1995 Mol. Cell Biol. 15: 2612–2624
Page DL, Ellis IO, Elson CW . 1995 Am. J. Clin. Pathol. 103: 123–124
Richter J, Wagner U, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T, Kallioniemi OP, Sauter G . 2000 Am. J. Pathol. 157: 787–794
Roos G, Nilsson P, Cajander S, Nielsen NH, Arnerlov C, Landberg G . 1998 Int. J. Cancer 21: 343–348
Schraml P, Kononen J, Bubendorf L, Moch H, Bissig H, Nocito A, Mihatsch MJ, Kallioniemi OP, Sauter G . 1999 Clin. Cancer Res. 5: 1966–1975
Sherr CJ . 1996 Science 6: 1672–1677
Sprenger CC, Damon SE, Hwa V, Rosenfeld RG, Plymate SR . 1999 Cancer Res. 59: 2370–2375
Spruck CH, Won KA, Reed SI . 1999 Nature 16: 297–300
Swisshelm K, Ryan K, Tsughya K, Sager R . 1995 Proc. Natl. Acad. Sci. USA 92: 4472–4476
Wilson EM, Oh Y, Rosenfeld RGJ . 1997 Clin. Endocrinol. Metab. 82: 1301–1303
Acknowledgements
We would like to thank Bodil Bäcklund and Britta Lindgren for skilful technical assistance and Martin Lodén for fruitful discussions. This work was supported by grants from the NCIC, Canadian Breast Cancer Research Initiative to A Seth and Swedish Cancer Society and Lion's Cancer research foundation, Umeå University to G Landberg.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Landberg, G., Östlund, H., Nielsen, N. et al. Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors. Oncogene 20, 3497–3505 (2001). https://doi.org/10.1038/sj.onc.1204471
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204471