Prolactin-induced protein

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. 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. PIP also binds to AZGP1.

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.

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. It is characteristic of low grade apocrine carcinoma of the breast, high grade apocrine carcinoma frequently lose expression of this marker. 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.

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

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

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.

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.

References

References

1. (July 1989). "The gene for prolactin-inducible protein (PIP), uniquely expressed in exocrine organs, maps to chromosome 7". Somat Cell Mol Genet.
2. (January 1992). "The prolactin-inducible protein (PIP/GCDFP-15) gene: cloning, structure and regulation". Mol Cell Endocrinol.
3. "Entrez Gene: PIP prolactin-induced protein".
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6. (February 2009). "Prolactin inducible protein in cancer, fertility and immunoregulation: structure, function and its clinical implications". Cell. Mol. Life Sci..
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9. (April 2002). "Identification of mouse submaxillary gland protein in mouse saliva and its binding to mouse oral bacteria". Arch. Oral Biol..
10. (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..
11. (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..
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13. (2006). "Comparative study of monoclonal antibody B72.3 and gross cystic disease fluid protein-15 as markers of apocrine carcinoma of the breast". APMIS.
14. (2009). "A functional and regulatory network associated with PIP expression in human breast cancer". PLOS ONE.
15. (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.
16. Lacroix M. (December 2006). "Significance, detection and markers of disseminated breast cancer cells". Endocr. Relat. Cancer.
17. (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..
18. (May 2012). "Runx2 controls a feed-forward loop between androgen and prolactin-induced protein (PIP) in stimulating T47D cell proliferation". J. Cell. Physiol..
19. (2012). "Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer". Breast Cancer Res..
20. (2013). "Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner". PLOS ONE.