In a previous study, infection with the mouse mammary tumor virus (MMTV) was shown to increase the sensitivity of the mammary epithelium toward prolactin (PRL); furthermore, this effect could be mimicked by the binding of the MMTV envelope protein (gp52) to its cell receptor. The present work has investigated the possibility that gp52-induced changes in the PRL receptor (PRLR) were responsible for this phenomenon. In vitro, gp52 doubled the PRLR concentration in the plasmalemma of mammary epithelium without affecting the affinity. The origins of these PRLRs were twofold: first, gp52 stimulated PRLR mRNA nearly fivefold, suggesting that some of the receptors were newly synthesized. Second, there was a redistribution of PRLRs within the mammary cell: PRLRs were shifted from an internal pool to the plasma membrane. This relocation was very rapid, occurring within 30 min. There did not appear to be any contribution from alterations in PRLR degradation, since the half-life of PRLR was not affected by gp52. In summary, the MMTV increases the PRL sensitivity of mouse mammary epithelium by elevating PRLRs through both enhanced synthesis and recruitment from microsomes.
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- Author: BK Vonderhaar x
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Bolander FF Jr, E Ginsburg, and BK Vonderhaar
JF Trott, RC Hovey, S Koduri, and BK Vonderhaar
Endocrine and autocrine prolactin (PRL) exerts effects on normal breast and breast cancer cells, and high serum PRL is a poor prognostic factor for colorectal cancer. Here we tested the hypothesis that short isoforms of the PRL receptor (PRLR) in human tissue regulate the actions of PRL in cancer. Using 3' RACE we isolated five splice variants of the human PRLR (hPRLR), three of which encode the complete extracellular binding domain. Two of these isoforms, short form 1a (SF1a) and short form 1b (SF1b), possess unique intracellular domains encoded by splicing to exon 11 from exons 10 and 9 respectively. A third novel isoform (delta7/11) reflects alternative splicing from exon 7 to exon 11 and encodes a secreted soluble PRL-binding protein. Additional splice variants of SF1b and delta7/11 that lacked exon 4 (delta4-SF1b and delta4-delta7/11) were also identified. Functional analyses indicated that hPRLR-SF1b is a strong dominant-negative to the differentiative function of the PRLR long form while hPRLR-SF1a is a weaker dominant-negative. Differential abundance of SF1a, SF1b and delta7/11 expression was detected in normal breast, colon, placenta, kidney, liver, ovary and pancreas, and breast and colon tumors. Taken together, these data indicate the presence of multiple isoforms of the hPRLR that may function to modulate the endocrine and autocrine effects of PRL in normal human tissue and cancer.
