title: A favorable role of prolactin in human breast cancer reveals novel pathway-based gene signatures indicative of tumor differentiation and favorable patient outcome.
abstract: Prolactin (PRL) hormone is known to play a key role in mammary gland development allowing for successful lactation. The role of this hormone in breast tumorigenesis is still controversial. Here, we evaluated PRL protein and gene expression levels in human breast cancer using tissue microarray of 100 breast cancer cases, as well as different publically available human breast cancer gene profiling databases. Interestingly, our results showed a significant downregulation of PRL expression in breast cancer compared to normal adjacent tissue. Moreover, expression of PRL was associated with more differentiated tumors, early stage, smaller tumor size and absence of distant metastasis. Importantly, our results indicate that higher PRL mRNA levels are significantly associated with prolonged relapse-free survival (RFS) in breast cancer patients (P=3.7 x 10(-9)). Additionally, examining expression of PRL pathway-based gene signature composed of PRL, PRLR, Jak2 and Stat5a showed a significant association with more differentiated tumors (P<.00001), prolonged RFS (P=1.8 x 10(-6)) as well as overall survival (OS) (P=.0026). As well, our results indicate that PRL-directed differentiation program in mammary epithelial cells offer good prognosis in human breast cancer. Indeed, expression of a gene signature composed of PRL-upregulated genes showed a significant association with well-differentiated tumors (P<.00001). Whereas expression of a gene signature composed of PRL-downregulated genes showed a significant association with shortened distant metastasis-free survival (DMFS) (P=.0086). Altogether our results highlight that PRL hormone and its signaling pathway may play an important role in maintaining tumor differentiation state and in turn better patient outcome.
authors.affiliation: Division of Hematology, Department of Medicine, Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University. Electronic address: Ibrahim.Hachim@mail.mcgill.ca.
authors.forename: Ibrahim Y
authors.initials: IY
authors.lastname: Hachim
authors.affiliation: Division of Hematology, Department of Medicine, Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University. Electronic address: Anwar.Shams@mail.mcgill.ca.
authors.forename: Anwar
authors.initials: A
authors.lastname: Shams
authors.affiliation: Division of Medical Oncology, Department of Medicine, Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University. Electronic address: JJ.Lebrun@mcgill.ca.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
authors.affiliation: Division of Hematology, Department of Medicine, Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University. Electronic address: Suhad.Ali@mcgill.ca.
authors.forename: Suhad
authors.initials: S
authors.lastname: Ali
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019295:Computational Biology; D030541:Databases, Genetic; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D011388:Prolactin / Q000235:genetics* / Q000378:metabolism; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046888:Tissue Array Analysis; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011981:Receptors, Prolactin; D011388:Prolactin
keywords: Differentiation; Gene signature; Jak/Stat; Mammary; Prognosis