BPIFA4P

Function

Although BPIFA4P is identified as a pseudogene in humans, the RNA sequence for a putative protein has been detected at moderate levels in several glands (including salivary and mammillary), skin, and breast cancer. That pattern is consistent with the expression of normal BPIFA4/Latherin found in saliva and sweat of other species such as cow, horse, and sheep. The function of BPIFA4 in those species is associated with BPIFA gene family members' properties of being a surfactant and binding to bacterial lipopolysaccharides. Sweat helps animals cool down, and in animals with pelts/fur BPIFA4/Latherin significantly reduces surface tension of sweat, acting as a wetting agent to facilitate evaporative cooling. Further, it is speculated that the presence of a surfactant protein in the saliva of ruminant animals (e.g., cow, horse, sheep) may assist in mastication of large quantities of vegetable matter in their diet. BPIFA4 in saliva also may function as a first line of defense against bacteria, via bactericidal functions similar to other BIPFA and BIPFB family members.

BASE Protein

The expression of a pseudogene product in humans has caused unresolved issues about BPIFA4 in humans. This uncommon situation was summarized by Bingle and colleagues at University of Sheffield, who did extensive work on the BPI/LBP/PLUNC family:

"Human BPIFA4 appears to be an example of a pseudogene (and should be properly identified as BPIFA4P) that is perhaps better described as a ‘dying’ gene, since it appears to be both transcribed and translated, but no longer encodes a functional protein product."

That non-functional protein came to be known as BASE (Breast cancer And Salivary gland Expression) protein. Using a screening method for identifying human genes that code for membrane proteins, researchers at the National Cancer Institute discovered in 2003 a previously uncharacterized gene in breast cancer cell lines. With RT-PCR and Northern blot techniques, they detected the expression of BASE RNA in several breast cancer cell lines but not normal breast tissue. Separately BASE RNA expression was found in salivary gland tumors and normal salivary gland tissue. Thus the acronym was devised to reflect that pattern. Investigators at EMBL subsequently confirmed BASE/BPIFA4P expression in ~50% of actual breast cancer tumor samples they tested. In particular, BASE/BPIFA4P expression was present in tumors with high levels of ERα estrogen receptor but not in tumors with low ERα. However, it was shown experimentally that estrogen represses the expression of the BASE/BPIFA4P gene, while the transcription factor FOXA1 activates the expression of BASE/BPIFA4P. The undetermined interplay between ERα and FOXA1 is likely to be important in hormone receptor-positive disease and acquired anti-hormone resistance. Although the BASE protein's potential function was never investigated, the presence of the BASE/BPIFA4P gene was nevertheless considered a potentially useful marker for breast cancer screening.

The BASE gene deposited into US and European databases was eventually recognized as being a member of the BPI/LBP/PLUNC family and subsequently relabeled as BPIFA4P. It was further recognized that unlike other primate genes for BPIFA4, the human BASE/BPIFA4P gene was missing a single nucleotide in exon 6. That deletion causes a frameshift mutation which results in a "premature" stop codon. The resulting human BASE protein is much shorter than the functional BPIFA4 and Latherin proteins of other species. The original analysis predicted the BASE protein to be 19.5 kDa in size, but Western blots show the protein migrates at a size larger than 22 kDa. This truncated human BASE protein lacks key structural elements of a functional BPIFA4 protein, namely a long α-helical segment that creates the BPI fold. Without that, BASE cannot function like any other BPI/LBP/PLUNC family member and is thus considered functionless.