The
prolactin receptor (PRLR) is a member of the lactogen/
cytokine receptor family, which mediates multiple actions of
prolactin (PRL). PRL is a major
hormone in the proliferation/differentiation of breast epithelium that is essential for lactation. It is also involved in
breast cancer development,
tumor growth and chemoresistance. Human PRLR expression is controlled at the transcriptional level by multiple promoters. Each promoter directs transcription/expression of a specific non-coding exon 1, a common non-coding exon 2 and coding exons E3-11. The identification of exon 11 of PRLR led to finding of alternative spliced products and two novel short forms (SF) that can inhibit the long form (LF) of PRLR activity with relevance in physiological regulation and
breast cancer. Homo and heterodimers of LF and SF are formed in the absence of PRL that acts as a conformational modifier. Heterodimerization of SF with LF is a major mechanism through which SF inhibits some signaling pathways originating at the LF. Biochemical/molecular modeling approaches demonstrated that the human PRLR conformation stabilized by extracellular intramolecular S-S bonds and several
amino acids in the extracellular D1 domain of PRLR SF are required for its inhibitory actions on PRLR LF-mediated functions. Studies in
breast cancer cells demonstrated that the transcription of PRLR was directed by the preferentially utilized PIII promoter, which lacks an
estrogen responsive
element. Complex formation of non-
DNA bound ERα dimer with Sp1 and C/EBPβ dimers bound to their sites at the PRLR promoter is required for basal activity.
Estradiol induces transcriptional activation/expression of the PRLR gene, and subsequent studies revealed the essential role of autocrine PRL released by
breast cancer cells and CDK7 in
estradiol-induced PRLR promoter activation and upregulation. Other studies revealed stimulation of the PRLR promoter activity and PRLR LF
protein by PRL in the absence of
estrogen via the STAT5/phospho-ERα activation loop. Additionally,
EGF/ERBB1 can induce the transcription of PRLR independent of
estrogen and
prolactin. The various regulatory modalities contributing to the upregulation of PRLR provide options for the development of therapeutic approaches to mitigate its participation in
breast cancer progression and resistance.