Prolactin-induced protein

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.[5][6][7] It is upregulated by prolactin and androgens and downregulated by estrogen.

PIP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPIP, GCDFP-15, GCDFP15, GPIP4, Prolactin-induced protein, prolactin induced protein, BRST-2
External IDsOMIM: 176720 MGI: 102696 HomoloGene: 1990 GeneCards: PIP
Orthologs
SpeciesHumanMouse
Entrez

5304

18716

Ensembl

ENSG00000159763

ENSMUSG00000058499

UniProt

P12273

P02816

RefSeq (mRNA)

NM_002652

NM_008843

RefSeq (protein)

NP_002643

NP_032869

Location (UCSC)Chr 7: 143.13 – 143.14 MbChr 6: 41.82 – 41.83 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8] 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.[9][10] PIP also binds to AZGP1.[10] PIP exerts aspartyl proteinase activity able to cleave fibronectin.[11][12]

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.[13][14]

Mitogenic effect of PIP was observed on both normal and malignant breast epithelial cells.[15]

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.[16][17] It is characteristic of low grade apocrine carcinoma of the breast, high grade apocrine carcinoma frequently lose expression of this marker.[18] 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.[19]

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.[20]

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.[21] In T47D breast cancer cells, androgen receptor and RUNX2 interact to synergistically enhance PIP expression.[22]

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.[23]

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.[24]

References
  1. GRCh38: Ensembl release 89: ENSG00000159763 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000058499 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Myal Y, Gregory C, Wang H, Hamerton JL, Shiu RP (July 1989). "The gene for prolactin-inducible protein (PIP), uniquely expressed in exocrine organs, maps to chromosome 7". Somat Cell Mol Genet. 15 (3): 265–70. doi:10.1007/BF01534877. PMID 2727805. S2CID 41577257.
  6. Myal Y, Robinson DB, Iwasiow B, Tsuyuki D, Wong P, Shiu RP (January 1992). "The prolactin-inducible protein (PIP/GCDFP-15) gene: cloning, structure and regulation". Mol Cell Endocrinol. 80 (1–3): 165–75. doi:10.1016/0303-7207(91)90153-J. PMID 1955075. S2CID 37888783.
  7. "Entrez Gene: PIP prolactin-induced protein".
  8. Mazoujian G, Pinkus GS, Davis S, Haagensen DE (February 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 (2): 105–12. PMC 1916150. PMID 6130702.
  9. Chiu WW, Chamley LW (December 2003). "Human seminal plasma prolactin-inducible protein is an immunoglobulin G-binding protein". J. Reprod. Immunol. 60 (2): 97–111. doi:10.1016/S0165-0378(03)00084-6. PMID 14638438.
  10. Hassan MI, Waheed A, Yadav S, Singh TP, Ahmad F (February 2009). "Prolactin inducible protein in cancer, fertility and immunoregulation: structure, function and its clinical implications". Cell. Mol. Life Sci. 66 (3): 447–59. doi:10.1007/s00018-008-8463-x. PMID 18854942. S2CID 5642491.
  11. Caputo E, Camarca A, Moharram R, Tornatore P, Thatcher B, Guardiola J, Martin BM (May 2003). "Structural study of GCDFP-15/gp17 in disease versus physiological conditions using a proteomic approach". Biochemistry. 42 (20): 6169–78. doi:10.1021/bi034038a. PMID 12755619.
  12. Caputo E, Manco G, Mandrich L, Guardiola J (March 2000). "A novel aspartyl proteinase from apocrine epithelia and breast tumors". J. Biol. Chem. 275 (11): 7935–41. doi:10.1074/jbc.275.11.7935. PMID 10713110.
  13. Lee B, Bowden GH, Myal Y (April 2002). "Identification of mouse submaxillary gland protein in mouse saliva and its binding to mouse oral bacteria". Arch. Oral Biol. 47 (4): 327–32. doi:10.1016/S0003-9969(01)00113-3. PMID 11922875.
  14. Schenkels LC, Walgreen-Weterings E, Oomen LC, Bolscher JG, Veerman EC, Nieuw Amerongen AV (February 1997). "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. doi:10.1515/bchm.1997.378.2.83. PMID 9088536. S2CID 23667673.
  15. Cassoni P, Sapino A, Haagensen DE, Naldoni C, Bussolati G (January 1995). "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. doi:10.1002/ijc.2910600215. PMID 7829219. S2CID 44775922.
  16. Collette J, Hendrick JC, Jaspar JM, Franchimont P (July 1986). "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. PMID 3486713.
  17. Petrakis NL, Lowenstein JM, Wiencke JK, Lee MM, Wrensch MR, King EB, Hilton JF, Miike R (1993). "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. PMID 8268776.
  18. Honma N, Takubo K, Arai T, Younes M, Kasumi F, Akiyama F, Sakamoto G (2006). "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. doi:10.1111/j.1600-0463.2006.apm_434.x. PMID 17004974. S2CID 21372161.
  19. Debily MA, Marhomy SE, Boulanger V, Eveno E, Mariage-Samson R, Camarca A, Auffray C, Piatier-Tonneau D, Imbeaud S (2009). "A functional and regulatory network associated with PIP expression in human breast cancer". PLOS ONE. 4 (3): e4696. Bibcode:2009PLoSO...4.4696D. doi:10.1371/journal.pone.0004696. PMC 2650800. PMID 19262752.
  20. Lacroix M (December 2006). "Significance, detection and markers of disseminated breast cancer cells". Endocr. Relat. Cancer. 13 (4): 1033–67. doi:10.1677/ERC-06-0001. PMID 17158753.
  21. 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 (November 2002). "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. doi:10.1093/hmg/11.23.2887. PMID 12393800.
  22. Baniwal SK, Little GH, Chimge NO, Frenkel B (May 2012). "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. doi:10.1002/jcp.22966. PMC 3376385. PMID 21809344.
  23. Naderi A, Meyer M (2012). "Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer". Breast Cancer Res. 14 (4): R111. doi:10.1186/bcr3232. PMC 3680918. PMID 22817771.
  24. Baniwal SK, Chimge NO, Jordan VC, Tripathy D, Frenkel B (2013). "Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner". PLOS ONE. 8 (6): e62361. Bibcode:2013PLoSO...862361B. doi:10.1371/journal.pone.0062361. PMC 3670933. PMID 23755096.

Further reading
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