Mutational analysis of the PRL receptor gene in human breast tumors with differential PRL receptor protein expression

PRL is a major growth and differentiating hormone in the human breast, with activation of the PRL-PRL receptor complex increasingly recognized as an i mportant mechanism in the induction and progression of mammary tumors. Alth ough constitutive activation of various hormone and growth factor receptors is newly recognized as a common cause of tumor development, the PRL recept or gene has not been analyzed for similar aberrations in breast and other t umors. Therefore, using bacterial artificial chromosomes containing the PRL receptor gene and intron-spanning PCR, we determined the exon-surrounding intron sequences providing primers for the first analysis of the entire cod ing region of the human PRL receptor gene. We examined the presence of PRL receptor in 41 breast tumors by immunohistochemistry and attempted a correl ation of its expression to pathological grading of the disease. Then tumor cells were isolated by laser capture microdissection to examine DNA from 30 patients for PRL receptor mutations. The PRL receptor immunoreactive score did not correlate to the tumor size, histopathological grading, age, or family history of patients. PRL receptor immunoreactivity was predominantly found in steroid hormone receptor-posit ive tumors, but without overall correlation of immunoreactive score. In bot h PRL receptor-positive and PRL receptor-negative breast cancer cells, dire ct sequencing of the coding sequence of the PRL receptor gene did not detec t any somatic or hereditary gene aberrations. In conclusion, PRL receptor mutations do not appear to be common in human b reast cancer, suggesting that constitutive activation of the PRL receptor c an be excluded as a major cause of mammary tumor genesis. The molecular str ucture of the PILL receptor seems to remain intact in tumor tissue, and sys temic and local production of PRL may participate in tumor cell growth and proliferation through functional receptors.