Abstract
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a 5-year disease-free survival of less than 45%. Little is known about the genetic alterations that result in IBC. In our previous work, we found that WISP3 was specifically lost in human IBC tumors when compared to stage-matched, non-IBC tumors. We hypothesize that WISP3 has tumor suppressor function in the breast and that it may be a key genetic alteration that contributes to the unique IBC phenotype. The full-length WISP3 cDNA was sequenced and cloned into an expression vector. The resulting construct was introduced in to the SUM149 cell line that was derived from a patient with IBC and lacks WISP3 expression. In soft agar, stable WISP3 transfectants formed significantly fewer colonies than the controls. Stable WISP3 transfectants lost their ability to invade and had reduced angiogenic potential. WISP3 transfection was effective in suppressing in vivo tumor growth in nude mice. Mice bearing WISP3 expressing tumors had a significantly longer survival than those with vector-control transfectant tumors. Our data demonstrate that WISP3 acts as a tumor suppressor gene in the breast. Loss of WISP3 expression contributes to the phenotype of IBC by regulating tumor cell growth, invasion and angiogenesis.
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Babic AM, Kireeva ML, Kolesnikova TV, Lau LF . 1998 Proc. Natl. Acad. Sci, USA 95: 6355–6360
Byun D, Mohan S, Baylink DJ, Qin X . 2001 J. Endocrinol. 169: 135–143
Ethier SP, Mahacek ML, Gullick WJ, Frank TS, Weber BL . 1993 Cancer Res. 53: 627–635
Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H, Yokota J . 1998 J. Exp. Med. 187: 289–296
Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML . 1999 Nat. Genet. 23: 94–98
Imai Y, Moralez A, Andag U, Clarke JB, Busby Jr WH, Clemmons DR . 2000 J. Biol. Chem. 275: 18188–18194
Jaiyesimi IA, Buzdar AU, Hortobagyi G . 1992 J. Clin. Oncol. 10: 1014–1024
Kalus W, Zweckstetter M, Renner C, Sanchez Y, Georgescu J, Grol M, Demuth D, Schumacher R, Dony C, Lang K, Holak TA . 1998 EMBO J. 17: 6558–6572
Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts Jr CT, Rosenfeld RG . 1997 Proc. Natl. Acad. Sci. USA 94: 12981–2986
Kireeva ML, Mo FE, Yang GP, Lau LF . 1996 Mol. Cell Biol. 16: 1326–1334
Lee BJaT ND . 1924 Surg. Gynecol. Obstet. 39: 580–595
Li W, Martinerie C, Zumkeller W . 1996 Mol. Pathol. 49: 91–97
Livant DL, Linn S, Markwart, Shuster J . 1995 Cancer Res. 55: 5085–5093
Lopez-Bermejo A, Buckway CK, Devi GR, Hwa V, Plymate SR, Oh Y, Rosenfeld RG . 2000 Endocrinology 141: 4072–4080
Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR . 1995 J. Exp. Med. 182: 1545–1556
Merajver SD, Weber BL, Cody R, Zhang D, Strawderman M, Calzone KA, LeClaire V, Levin A, Irani J, Halvie M, August D, Wicha M, Lichter A, Pierce LJ . 1997 J. Clin. Oncol. 15: 2873–2881
Nissanov J, Tuman RW, Gruver LM, Fortunato JM . 1995 Lab. Invest. 73: 734–739
O'Brien TP, Lau LF . 1992 Cell Growth Differ. 3: 645–654
Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG . 1996 J. Biol. Chem. 271: 30322–30325
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ . 1998 Proc. Natl. Acad. Sci. USA 95: 14717–14722
Perbal B . 2001 Mol. Pathol. 54: 57–79
Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD . 2001 Nature 409: 633–637
Sprenger CC, Damon SE, Hwa V, Rosenfeld RG, Plymate SR . 1999 Cancer Res. 59: 2370–2375
Swain SM, Sorace RA, Bagley CS, Danforth Jr DN, Bader J, Wesley MN, Steinberg SM, Lippman ME . 1987 Cancer Res. 47: 3889–3894
Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R, Fei YL, Mondal S, Ivanchuk S, Ackerley C, Hamel PA, Rutka JT . 2000 Am. J. Pathol. 157: 919–932
van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP, Merajver SD . 1999 Clin. Cancer Res. 5: 2511–2519
van Golen KL, Wu ZF, Qiao XT, Bao L, Merajver SD . 2000a Neoplasia 2: 418–425
van Golen KL, Wu ZF, Qiao XT, Bao LW, Merajver SD . 2000b Cancer Res. 60: 5832–5838
Wong M, Kireeva ML, Kolesnikova TV, Lau LF . 1997 Dev. Biol. 192: 492–508
Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ . 2000 Genes Dev. 14: 585–595
Acknowledgements
We thank Wendy Kutz and Matthew Warman from Case Western Reserve University for providing anti-WISP3 polyclonal antibody. We thank Satoru Hayasaka for statistical support, and Elizabeth Horn and Robin Kunkel for artwork. Work supported in part by DOD grant DAMD17-00-1-0636 (CG Kleer), and NIH grants RO1CA77612 (SD Merajver), P30CA46592, M01-RR00042 and DAMD17-00-0345 (SD Merajver).
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Kleer, C., Zhang, Y., Pan, Q. et al. WISP3 is a novel tumor suppressor gene of inflammatory breast cancer. Oncogene 21, 3172–3180 (2002). https://doi.org/10.1038/sj.onc.1205462
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DOI: https://doi.org/10.1038/sj.onc.1205462
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