Prolactin-induced protein explained

Prolactin-inducible protein also known as gross cystic disease fluid protein 15 (GCDFP-15), extra-parotid glycoprotein (EP-GP), gp17 seminal actin-binding protein (SABP) or BRST2 is a protein that in humans is encoded by the PIP gene.^{[1] [2] [3]} It is upregulated by prolactin and androgens and downregulated by estrogen.

Function

The protein has a physiological function in regulation of water transport mainly in apocrine glands in the axilla, vulva, eyelid and ear canal, serous cells of the submandibular salivary gland, serous cells of the submucosal glands of the bronchi, and accessory lacrimal glands as well as cutaneous eccrine glands.^[4] It is also found in amniotic fluid and seminal fluid. PIP has the ability to bind immunoglobulin G (IgG), IgG-Fc, CD4-T cell receptor suggesting a wide range of immunological functions.^{[5] [6]} PIP also binds to AZGP1.^[6] PIP exerts aspartyl proteinase activity able to cleave fibronectin.^{[7] [8]}

PIP can bind different species of bacteria showing highest affinity to streptococci thus playing a role in non-immune defense of the body against pathogenic bacterial strains.^{[9] [10]}

Mitogenic effect of PIP was observed on both normal and malignant breast epithelial cells.

Use as marker and significance in disease

Prolactin induced protein (called GCDFP-15 in this context) in breast cyst fluid or breast tissue serves as marker of both benign and malignant apocrine metaplasia as the protein is not normally expressed in breast tissue.^{[11] [12]} It is characteristic of low grade apocrine carcinoma of the breast, high grade apocrine carcinoma frequently lose expression of this marker.^[13] PIP gene expression in breast cancer lines was associated with decreased cell proliferation and invasiveness and an increase of the apoptotic pathway. Many of the genes affected by PIP appear to be regulated by STAT5.^[14]

A mitogenic effect of this protein on experimental breast cells lines MCF10A, MCF7, BT474, MDA-MB231 and T47D was detected.^[15] Prolactin-induced protein has also been used for identification and detection of disseminated breast cancer cells.^[16]

The PIP gene is amplified in some breast cancer lines accounting for some of its overexpression, however additional mechanisms are needed to completely explain its overexpression.^[17] In T47D breast cancer cells, androgen receptor and RUNX2 interact to synergistically enhance PIP expression.^[18]

In molecular apocrine breast cancer (ER-/AR+) there is a positive feedback loop between androgen receptor and extracellular signal-regulated kinase (ERK) via CREB1 which can be inhibited by anti-androgens. PIP expression is necessary for viability and invasiveness of this subtype of breast cancer.^[19]

In ER+ breast cancer, particularly those with very high level of ER expression, PIP appears to play an important role in proliferation and invasion as well as acquired resistance to tamoxifen.^[20]

Further reading

• Schaller J, Akiyama K, Kimura H, etal . Primary structure of a new actin-binding protein from human seminal plasma . Eur. J. Biochem. . 196 . 3 . 743–50 . 1991 . 2013294 . 10.1111/j.1432-1033.1991.tb15873.x . free .
• Murphy LC, Tsuyuki D, Myal Y, Shiu RP . 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 . 31 . 15236–41 . 1987 . 10.1016/S0021-9258(18)48164-1 . 3667631 . free .
• Touchman JW, Bouffard GG, Weintraub LA, etal . 2006 expressed-sequence tags derived from human chromosome 7-enriched cDNA libraries . Genome Res. . 7 . 3 . 281–92 . 1997 . 9074931 . 10.1101/gr.7.3.281 . free .
• Autiero M, Bouchier C, Basmaciogullari S, etal . Isolation from a human seminal vesicle library of the cDNA for gp17, a CD4 binding factor . Immunogenetics . 46 . 4 . 345–8 . 1997 . 9218538 .
• Caputo E, Autiero M, Mani JC, etal . Differential antibody reactivity and CD4 binding of the mammary tumor marker protein GCDFP-15 from breast cyst and its counterparts from exocrine epithelia . Int. J. Cancer . 78 . 1 . 76–85 . 1998 . 9724097 . 10.1002/(SICI)1097-0215(19980925)78:1<76::AID-IJC13>3.0.CO;2-3 . free .
• Gaubin M, Autiero M, Basmaciogullari S, etal . Potent inhibition of CD4/TCR-mediated T cell apoptosis by a CD4-binding glycoprotein secreted from breast tumor and seminal vesicle cells . J. Immunol. . 162 . 5 . 2631–8 . 1999 . 10.4049/jimmunol.162.5.2631 . 10072505 .
• Caputo E, Manco G, Mandrich L, Guardiola J . A novel aspartyl proteinase from apocrine epithelia and breast tumors . J. Biol. Chem. . 275 . 11 . 7935–41 . 2000 . 10713110 . 10.1074/jbc.275.11.7935 . free .
• Basmaciogullari S, Autiero M, Culerrier R, etal . Mapping the CD4 binding domain of gp17, a glycoprotein secreted from seminal vesicles and breast carcinomas . Biochemistry . 39 . 18 . 5332–40 . 2000 . 10820003 . 10.1021/bi992398l .
• Rieske P, Pongubala JM . AKT induces transcriptional activity of PU.1 through phosphorylation-mediated modifications within its transactivation domain . J. Biol. Chem. . 276 . 11 . 8460–8 . 2001 . 11133986 . 10.1074/jbc.M007482200 . free.
• Autiero M, Camarca A, Ciullo M, etal . Intragenic amplification and formation of extrachromosomal small circular DNA molecules from the PIP gene on chromosome 7 in primary breast carcinomas . Int. J. Cancer . 99 . 3 . 370–7 . 2002 . 11992405 . 10.1002/ijc.10368 . 30723802 . free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Scherer SW, Cheung J, MacDonald JR, etal . Human chromosome 7: DNA sequence and biology . Science . 300 . 5620 . 767–72 . 2003 . 12690205 . 2882961 . 10.1126/science.1083423 . 2003Sci...300..767S .
• Caputo E, Camarca A, Moharram R, etal . Structural study of GCDFP-15/gp17 in disease versus physiological conditions using a proteomic approach . Biochemistry . 42 . 20 . 6169–78 . 2003 . 12755619 . 10.1021/bi034038a .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Shishioh N, Hong Y, Ohishi K, etal . GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol . J. Biol. Chem. . 280 . 10 . 9728–34 . 2005 . 15632136 . 10.1074/jbc.M413755200 . free .
• Rual JF, Venkatesan K, Hao T, etal . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Ramachandran P, Boontheung P, Xie Y, etal . Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry . J. Proteome Res. . 5 . 6 . 1493–503 . 2006 . 16740002 . 10.1021/pr050492k .
• Ewing RM, Chu P, Elisma F, etal . Large-scale mapping of human protein-protein interactions by mass spectrometry . Mol. Syst. Biol. . 3 . 1. 89 . 2007 . 17353931 . 10.1038/msb4100134 . 1847948 .
• Lee B, Bowden GH, Myal Y . Identification of mouse submaxillary gland protein in mouse saliva and its binding to mouse oral bacteria . Arch Oral Biol . 47 . 4 . 327–32 . 2002 . 11922875 . 10.1016/S0003-9969(01)00113-3 .
• Schenkels LC, Walgreen-Weterings E, Oomen LC, Bolscher JG, Veerman EC, Nieuw Amerongen AV . In vivo binding of the salivary glycoprotein EP-GP (identical to GCDFP-15) to oral and non-oral bacteria detection and identification of EP-GP binding species . Biol. Chem. . 378 . 2 . 83–8 . 1997 . 9088536 . 10.1515/bchm.1997.378.2.83 . 23667673 .

External links

• BRST2 immunostaining - abcam.com.
• GCDFP-15 immunostaining - immunosaver.com.

Notes and References

1. Myal Y, Gregory C, Wang H, Hamerton JL, Shiu RP . The gene for prolactin-inducible protein (PIP), uniquely expressed in exocrine organs, maps to chromosome 7 . Somat Cell Mol Genet . 15 . 3 . 265–70 . July 1989 . 2727805 . 10.1007/BF01534877 . 41577257 .
2. Myal Y, Robinson DB, Iwasiow B, Tsuyuki D, Wong P, Shiu RP . The prolactin-inducible protein (PIP/GCDFP-15) gene: cloning, structure and regulation . Mol Cell Endocrinol . 80 . 1–3 . 165–75 . January 1992 . 1955075 . 10.1016/0303-7207(91)90153-J . 37888783 .
3. Web site: Entrez Gene: PIP prolactin-induced protein.
4. Geraldine Pinkus . Mazoujian G, Pinkus GS, Davis S, Haagensen DE . 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 . 2 . 105–12 . February 1983 . 6130702 . 1916150 .
5. Chiu WW, Chamley LW . Human seminal plasma prolactin-inducible protein is an immunoglobulin G-binding protein . J. Reprod. Immunol. . 60 . 2 . 97–111 . December 2003 . 14638438 . 10.1016/S0165-0378(03)00084-6.
6. Hassan MI, Waheed A, Yadav S, Singh TP, Ahmad F . Prolactin inducible protein in cancer, fertility and immunoregulation: structure, function and its clinical implications . Cell. Mol. Life Sci. . 66 . 3 . 447–59 . February 2009 . 18854942 . 10.1007/s00018-008-8463-x . 5642491 . 11131491 .
7. Caputo E, Camarca A, Moharram R, Tornatore P, Thatcher B, Guardiola J, Martin BM . Structural study of GCDFP-15/gp17 in disease versus physiological conditions using a proteomic approach . Biochemistry . 42 . 20 . 6169–78 . May 2003 . 12755619 . 10.1021/bi034038a .
8. Caputo E, Manco G, Mandrich L, Guardiola J . A novel aspartyl proteinase from apocrine epithelia and breast tumors . J. Biol. Chem. . 275 . 11 . 7935–41 . March 2000 . 10713110 . 10.1074/jbc.275.11.7935 . free .
9. Lee B, Bowden GH, Myal Y . Identification of mouse submaxillary gland protein in mouse saliva and its binding to mouse oral bacteria . Arch. Oral Biol. . 47 . 4 . 327–32 . April 2002 . 11922875 . 10.1016/S0003-9969(01)00113-3.
10. Schenkels LC, Walgreen-Weterings E, Oomen LC, Bolscher JG, Veerman EC, Nieuw Amerongen AV . In vivo binding of the salivary glycoprotein EP-GP (identical to GCDFP-15) to oral and non-oral bacteria detection and identification of EP-GP binding species . Biol. Chem. . 378 . 2 . 83–8 . February 1997 . 9088536 . 10.1515/bchm.1997.378.2.83. 23667673 .
11. Collette J, Hendrick JC, Jaspar JM, Franchimont P . Presence of alpha-lactalbumin, epidermal growth factor, epithelial membrane antigen, and gross cystic disease fluid protein (15,000 daltons) in breast cyst fluid . Cancer Res. . 46 . 7 . 3728–33 . July 1986 . 3486713 .
12. Petrakis NL, Lowenstein JM, Wiencke JK, Lee MM, Wrensch MR, King EB, Hilton JF, Miike R . Gross cystic disease fluid protein in nipple aspirates of breast fluid of Asian and non-Asian women . Cancer Epidemiol. Biomarkers Prev. . 2 . 6 . 573–9 . 1993 . 8268776 .
13. Honma N, Takubo K, Arai T, Younes M, Kasumi F, Akiyama F, Sakamoto G . Comparative study of monoclonal antibody B72.3 and gross cystic disease fluid protein-15 as markers of apocrine carcinoma of the breast . APMIS . 114 . 10 . 712–9 . 2006 . 17004974 . 10.1111/j.1600-0463.2006.apm_434.x . 21372161 .
14. Debily MA, Marhomy SE, Boulanger V, Eveno E, Mariage-Samson R, Camarca A, Auffray C, Piatier-Tonneau D, Imbeaud S . A functional and regulatory network associated with PIP expression in human breast cancer . PLOS ONE . 4 . 3 . e4696 . 2009 . 19262752 . 2650800 . 10.1371/journal.pone.0004696 . 2009PLoSO...4.4696D . free .
15. Cassoni P, Sapino A, Haagensen DE, Naldoni C, Bussolati G . Mitogenic effect of the 15-kDa gross cystic disease fluid protein (GCDFP-15) on breast-cancer cell lines and on immortal mammary cells . Int. J. Cancer . 60 . 2 . 216–20 . January 1995 . 7829219 . 10.1002/ijc.2910600215. 44775922 .
16. Lacroix M . Significance, detection and markers of disseminated breast cancer cells . Endocr. Relat. Cancer . 13 . 4 . 1033–67 . December 2006 . 17158753 . 10.1677/ERC-06-0001 . 10708900 . Marc Lacroix (biochemist) .
17. Ciullo M, Debily MA, Rozier L, Autiero M, Billault A, Mayau V, El Marhomy S, Guardiola J, Bernheim A, Coullin P, Piatier-Tonneau D, Debatisse M . Initiation of the breakage-fusion-bridge mechanism through common fragile site activation in human breast cancer cells: the model of PIP gene duplication from a break at FRA7I . Hum. Mol. Genet. . 11 . 23 . 2887–94 . November 2002 . 12393800 . 10.1093/hmg/11.23.2887. free .
18. Baniwal SK, Little GH, Chimge NO, Frenkel B . Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation . J. Cell. Physiol. . 227 . 5 . 2276–82 . May 2012 . 21809344 . 10.1002/jcp.22966 . 3376385 .
19. Naderi A, Meyer M . Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer . Breast Cancer Res. . 14 . 4 . R111 . 2012 . 22817771 . 3680918 . 10.1186/bcr3232 . free .
20. Baniwal SK, Chimge NO, Jordan VC, Tripathy D, Frenkel B . Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner . PLOS ONE . 8 . 6 . e62361 . 2013 . 23755096 . 3670933 . 10.1371/journal.pone.0062361 . 2013PLoSO...862361B . free .