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Mutational Analysis of the PRL Receptor Gene in Human Breast Tumors with Differential PRL Receptor Protein Expression

Children’s Hospital, University of Leipzig (A.G.), 04317 Leipzig, Germany; Institute of Pathology, University of Leipzig (L.-C.H.), 04103 Leipzig, Germany; Hospital St. Georg (U.K.), 04129 Leipzig, Germany; Faculté de Médicine Necker, INSERM, U-344 (P.A.K.), 75730 Paris, France; Unit on Genetics and Endocrinology, Developmental Endocrinology Branch (S.E.T., C.A.S.), National Institute of Child Health and Human Development, and Department of Pathology (J.G.) and Laboratory of Tumor Immunology and Biology, Molecular and Cellular Endocrinology Section (B.K.V.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Endocrinology (S.R.B.), University of Duesseldorf, D-40225 Duesseldorf, Germany

Address all correspondence and requests for reprints to: Annegret Glasow, Ph.D., Leukaemia Research Fund Center at the Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, United Kingdom SW3 6JB. E-mail: aglasow{at}icr.ac.uk

Abstract

PRL is a major growth and differentiating hormone in the human breast, with activation of the PRL-PRL receptor complex increasingly recognized as an important mechanism in the induction and progression of mammary tumors. Although constitutive activation of various hormone and growth factor receptors is newly recognized as a common cause of tumor development, the PRL receptor gene has not been analyzed for similar aberrations in breast and other tumors. 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 coding region of the human PRL receptor gene. We examined the presence of PRL receptor in 41 breast tumors by immunohistochemistry and attempted a correlation 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-positive tumors, but without overall correlation of immunoreactive score. In both PRL receptor-positive and PRL receptor- negative breast cancer cells, direct sequencing of the coding sequence of the PRL receptor gene did not detect any somatic or hereditary gene aberrations.

In conclusion, PRL receptor mutations do not appear to be common in human breast cancer, suggesting that constitutive activation of the PRL receptor can be excluded as a major cause of mammary tumor genesis. The molecular structure of the PRL receptor seems to remain intact in tumor tissue, and systemic and local production of PRL may participate in tumor cell growth and proliferation through functional receptors.

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