Chemistry:Prolactin-induced protein

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[11]

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.[12][13] It is characteristic of low grade apocrine carcinoma of the breast, high grade apocrine carcinoma frequently lose expression of this marker.[14] 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.[15]

A mitogenic effect of this protein on experimental breast cells lines MCF10A, MCF7, BT474, MDA-MB231 and T47D was detected.[11] 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]

References

  1. ↑ "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. doi:10.1007/BF01534877. PMID 2727805. 
  2. ↑ "The prolactin-inducible protein (PIP/GCDFP-15) gene: cloning, structure and regulation". Mol Cell Endocrinol 80 (1–3): 165–75. January 1992. doi:10.1016/0303-7207(91)90153-J. PMID 1955075. 
  3. ↑ "Entrez Gene: PIP prolactin-induced protein". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5304. 
  4. ↑ "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. PMID 6130702. 
  5. ↑ "Human seminal plasma prolactin-inducible protein is an immunoglobulin G-binding protein". J. Reprod. Immunol. 60 (2): 97–111. December 2003. doi:10.1016/S0165-0378(03)00084-6. PMID 14638438. 
  6. ↑ 6.0 6.1 "Prolactin inducible protein in cancer, fertility and immunoregulation: structure, function and its clinical implications". Cell. Mol. Life Sci. 66 (3): 447–59. February 2009. doi:10.1007/s00018-008-8463-x. PMID 18854942. 
  7. ↑ "Structural study of GCDFP-15/gp17 in disease versus physiological conditions using a proteomic approach". Biochemistry 42 (20): 6169–78. May 2003. doi:10.1021/bi034038a. PMID 12755619. 
  8. ↑ "A novel aspartyl proteinase from apocrine epithelia and breast tumors". J. Biol. Chem. 275 (11): 7935–41. March 2000. doi:10.1074/jbc.275.11.7935. PMID 10713110. 
  9. ↑ "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. doi:10.1016/S0003-9969(01)00113-3. PMID 11922875. 
  10. ↑ "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. doi:10.1515/bchm.1997.378.2.83. PMID 9088536. 
  11. ↑ 11.0 11.1 "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. doi:10.1002/ijc.2910600215. PMID 7829219. 
  12. ↑ "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. PMID 3486713. 
  13. ↑ "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. PMID 8268776. 
  14. ↑ "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. doi:10.1111/j.1600-0463.2006.apm_434.x. PMID 17004974. 
  15. ↑ "A functional and regulatory network associated with PIP expression in human breast cancer". PLOS ONE 4 (3): e4696. 2009. doi:10.1371/journal.pone.0004696. PMID 19262752. Bibcode: 2009PLoSO...4.4696D. 
  16. ↑ 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. 
  17. ↑ "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. doi:10.1093/hmg/11.23.2887. PMID 12393800. 
  18. ↑ "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. doi:10.1002/jcp.22966. PMID 21809344. 
  19. ↑ "Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer". Breast Cancer Res. 14 (4): R111. 2012. doi:10.1186/bcr3232. PMID 22817771. 
  20. ↑ "Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner". PLOS ONE 8 (6): e62361. 2013. doi:10.1371/journal.pone.0062361. PMID 23755096. Bibcode: 2013PLoSO...862361B. 

Further reading

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