Summary
The prolactin-inducible protein (PIP/GCPD15) is believed to originate from a limited set of tissues, including breast and salivary glands, and has been applied as a clinical marker for the diagnosis of metastatic tumours of unknown origin. We have investigated the potential role of PIP mRNA as a marker of human breast cancer metastasis. Using reverse transcription polymerase chain reaction and Southern or dot blot analysis, PIP mRNA was detected in 4/6 breast cell lines, independent of oestrogen receptor (ER) status. In breast primary tumours (n = 97), analysed from histologically characterized sections, PIP mRNA was detected in most cases. Higher PIP mRNA levels correlated with ER+ (P = 0.0004), progesterone receptor positive (PR+) (P = 0.0167), low-grade (P = 0.0195) tumours, and also PIP protein levels assessed by immunohistochemistry (n = 19, P = 0.0319). PIP mRNA expression was also detectable in 11/16 (69%) of axillary node metastases. PIP mRNA expression, however, was also detected in normal breast duct epithelium, skin, salivary gland and peripheral blood leucocyte samples from normal individuals. We conclude that PIP mRNA is frequently expressed in both primary human breast tumours and nodal metastases. However, the presence of PIP expression in skin creates a potential source of contamination in venepuncture samples that should be considered in its application as a marker for breast tumour micrometastases.
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16 November 2011
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References
Bostick, PJ, Chatterjee, S, Chi, DD, Huynh, KT, Giuliano, AE, Cote, R & Hoon, DS (1998). Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. J Clin Oncol 16: 2632–2640.
Bundred, NJ, Stewart, HJ, Shaw, DA, Forrest, AP & Miller, WR (1990). Relation between apocrine differentiation and receptor status, prognosis and hormonal response in breast cancer. Eur J Cancer 26: 1145–117.
de Almeida, PC & Pestana, CB (1992). Immunohistochemical markers in the identification of metastatic breast cancer. Breast Cancer Res Treat 21: 201–210.
de Graaf, H, Maelandsmo, GM, Ruud, P, Forus, A, Oyjord, T, Fodstad, O & Hovig, E (1997). Ectopic expression of target genes may represent an inherent limitation of RT-PCR assays used for micrometastasis detection: studies on the epithelial glycoprotein gene EGP-2. Int J Cancer 72: 191–196.
Dingemans, AM, Brakenhoff, RH, Postmus, PE & Giaccone, G (1997). Detection of cytokeratin-19 transcripts by reverse transcriptase-polymerase chain reaction in lung cancer cell lines and blood of lung cancer patients [see comments]. Lab Invest 77: 213–220.
Elston, CW & Ellis, IO (1991). Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19: 403–410.
Ercolani, L, Florence, B, Denaro, M & Alexander, M (1988). Isolation and complete sequence of a functional human glyceraldehyde-3-phosphate dehydrogenase gene. J Biol Chem 263: 15335–15341.
Ferrari, AC, Stone, NN, Eyler, JN, Gao, M, Mandeli, J, Unger, P, Gallagher, RE & Stock, R (1997). Prospective analysis of prostate-specific markers in pelvic lymph nodes of patients with high-risk prostate cancer [see comments]. J Natl Cancer Inst 89: 1498–1504.
Fiel, MI, Cernaianu, G, Burstein, DE & Batheja, N (1996). Value of GCDFP-15 (BRST-2) as a specific immunocytochemical marker for breast carcinoma in cytologic specimens. Acta Cytol 40: 637–641.
Haagensen, DE, Dilley Jr., WG, Mazoujian, G & Wells, SA, Jr (1990). Review of GCDFP-15. An apocrine marker protein. Ann NY Acad Sci 586: 161–173.
Hall, RE, Clements, JA, Birrell, SN & Tilley, WD (1998). Prostate-specific antigen and gross cystic disease fluid protein-15 are co-expressed in androgen receptor-positive breast tumours. Br J Cancer 78: 360–365.
Hiller, T, Snell, L & Watson, PH (1996). Microdissection RT-PCR analysis of gene expression in pathologically defined frozen tissue sections. Biotechniques 21: 38–40, 42, 44.
Hoon, DS, Sarantou, T, Doi, F, Chi, DD, Kuo, C, Conrad, AJ, Schmid, P, Turner, R & Guiliano, A (1996). Detection of metastatic breast cancer by beta-hCG polymerase chain reaction. Int J Cancer 69: 369–374.
Leygue, E, Snell, L, Hiller, T, Dotzlaw, H, Hole, K, Murphy, LC & Watson, PH (1996). Differential expression of psoriasin messenger RNA between in situ and invasive human breast carcinoma [published erratum appears in Cancer Res 1997 Feb 15; 57(4): 793]. Cancer Res 56: 4606–4609.
Lockett, MA, Baron, PL, PH, OB, Elliott, BM, Robison, JG, Maitre, N, Metcalf, JS & Cole, DJ (1998a). Detection of occult breast cancer micrometastases in axillary lymph nodes using a multimarker reverse transcriptase-polymerase chain reaction panel. J Am Coll Surg 187: 9–16.
Lockett, MA, Metcalf, JS, Baron, PL, PH, OB, Elliott, BM, Robison, JG & Cole, DJ (1998b). Efficacy of reverse transcriptase-polymerase chain reaction screening for micrometastic disease in axillary lymph nodes of breast cancer patients. Am Surg 64: 539–543; discussion 543–544.
Lopez-Guerrero, JA, Bolufer-Gilabert, P, Sanz-Alonso, M, Barragan-Gonzalez, E, Palau-Perez, J, De la Rubia-Comos, J, Sempere-Talens, A & Bonanad-Boix, S (1997). Minimal illegitimate levels of cytokeratin K19 expression in mononucleated blood cells detected by a reverse transcription PCR method (RT-PCR). Clin Chim Acta 263: 105–116.
Manni, A, Santen, RJ, Boucher, AE, Lipton, A, Harvey, H, Drago, J, Rohner, T, Haagensen, D, Glode, M & Santner, SJ (1984). Evaluation of CEA and GCDFP-15 plasma level during hormonally induced cancer stimulation. Anticancer Res 4: 141–144.
Mazoujian, G, Bodian, C, Haagensen, DE & Haagensen Jr., CD (1989). Expression of GCDFP-15 in breast carcinomas. Relationship to pathologic and clinical factors. Cancer 63: 2156–2161.
Mazoujian, G, Pinkus, GS, Davis, S & Haagensen, DE, Jr (1983). Immunohistochemistry of a gross cystic disease fluid protein (GCDFP-15) of the breast. A marker of apocrine epithelium and breast carcinomas with apocrine features. Am J Pathol 110: 105–112.
McGuckin, MA, Cummings, MC, Walsh, MD, Hohn, BG, Bennett, IC & Wright, RG (1996). Occult axillary node metastases in breast cancer: their detection and prognostic significance. Br J Cancer 73: 88–95.
Min, CJ, Tafra, L & Verbanac, KM (1998). Identification of superior markers for polymerase chain reaction detection of breast cancer metastases in sentinel lymph nodes [In Process Citation]. Cancer Res 58: 4581–4584.
Monteagudo, C, Merino, MJ, LaPorte, N & Neumann, RD (1991). Value of gross cystic disease fluid protein-15 in distinguishing metastatic breast carcinomas among poorly differentiated neoplasms involving the ovary. Hum Pathol 22: 368–372.
Mori, M, Mimori, K, Ueo, H, Karimine, N, Barnard, GF, Sugimachi, K & Akiyoshi, T (1996). Molecular detection of circulating solid carcinoma cells in the peripheral blood: the concept of early systemic disease. Int J Cancer 68: 739–743.
Murphy, LC, Lee-Wing, M, Goldenberg, GJ & Shiu, RP (1987a). Expression of the gene encoding a prolactin-inducible protein by human breast cancers in vivo: correlation with steroid receptor status. Cancer Res 47: 4160–4164.
Murphy, LC, Tsuyuki, D, Myal, Y & Shiu, RP (1987b). Isolation and sequencing of a cDNA clone for a prolactin-inducible protein (PIP). Regulation of PIP gene expression in the human breast cancer cell line, T-47D. J Biol Chem 262: 15236–15241.
Noguchi, S, Aihara, T, Nakamori, S, Motomura, K, Inaji, H, Imaoka, S & Koyama, H (1994). The detection of breast carcinoma micrometastases in axillary lymph nodes by means of reverse transcriptase-polymerase chain reaction. Cancer 74: 1595–1600.
Noguchi, S, Aihara, T, Motomura, K, Inaji, H, Imaoka, S & Koyama, H (1996). Detection of breast cancer micrometastases in axillary lymph nodes by means of reverse transcriptase-polymerase chain reaction. Comparison between MUC1 mRNA and keratin 19 mRNA amplification. Am J Pathol 148: 649–656.
Ormsby, AH, Snow, JL, Su, WP & Goellner, JR (1995). Diagnostic immunohistochemistry of cutaneous metastatic breast carcinoma: a statistical analysis of the utility of gross cystic disease fluid protein-15 and estrogen receptor protein. J Am Acad Dermatol 32: 711–716.
Pagani, A, Sapino, A, Eusebi, V, Bergnolo, P & Bussolati, G (1994). PIP/GCDFP-15 gene expression and apocrine differentiation in carcinomas of the breast. Virchows Arch 425: 459–465.
Pelkey, TJ, Frierson, HF Jr & Bruns, DE (1996). Molecular and immunological detection of circulating tumor cells and micrometastases from solid tumors. Clin Chem 42: 1369–1381.
Raj, GV, Moreno, JG & Gomella, LG (1998). Utilization of polymerase chain reaction technology in the detection of solid tumors. Cancer 82: 1419–1442.
Schoenfeld, A, Kruger, KH, Gomm, J, Sinnett, HD, Gazet, JC, Sacks, N, Bender, HG, Luqmani, Y & Coombes, RC (1997). The detection of micrometastases in the peripheral blood and bone marrow of patients with breast cancer using immunohistochemistry and reverse transcriptase polymerase chain reaction for keratin 19. Eur J Cancer 33: 854–861.
Soomro, S & Shousha, S (1992). Monoclonal antibody B72.3 immunostaining of breast carcinoma. Patterns of staining and relationship to mucin content and GCDFP-15 reactivity. Arch Pathol Lab Med 116: 32–35.
Tsuchiya, A, Sugano, K, Kimijima, I & Abe, R (1996). Immunohistochemical evaluation of lymph node micrometastases from breast cancer. Acta Oncol 35: 425–428.
Vary, CP, Carmody, M, LeBlanc, R, Hayes, T, Rundell, C & Keilson, L (1996). Allele-specific hybridization of lipoprotein lipase and factor-V Leiden missense mutations with direct label alkaline phosphatase-conjugated oligonucleotide probes. Genet Anal 13: 59–65.
Viacava, P, Naccarato, AG & Bevilacqua, G (1998). Spectrum of GCDFP-15 expression in human fetal and adult normal tissues. Virchows Arch 432: 255–260.
Watson, PH, Snell, L & Parisien, M (1996). The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research. Cmaj 155: 281–283.
Wick, MR, Lillemoe, TJ, Copland, GT, Swanson, PE, Manivel, JC & Kiang, DT (1989). Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol 20: 281–287.
Wick, MR, Ockner, DM, Mills, SE, Ritter, JH & Swanson, PE (1998). Homologous carcinomas of the breasts, skin, and salivary glands. A histologic and immunohistochemical comparison of ductal mammary carcinoma, ductal sweat gland carcinoma, and salivary duct carcinoma. Am J Clin Pathol 109: 75–84.
Zippelius, A, Kufer, P, Honold, G, Kollermann, MW, Oberneder, R, Schlimok, G, Riethmuller, G & Pantel, K (1997). Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol 15: 2701–2708.
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Clark, J., Snell, L., Shiu, R. et al. The potential role for prolactin-inducible protein (PIP) as a marker of human breast cancer micrometastasis. Br J Cancer 81, 1002–1008 (1999). https://doi.org/10.1038/sj.bjc.6690799
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DOI: https://doi.org/10.1038/sj.bjc.6690799
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