title: Mammary glands exhibit molecular laterality and undergo left-right asymmetric ductal epithelial growth in MMTV-cNeu mice.
abstract: Significant left-right (L-R) differences in tumor incidence and disease outcome occur for cancers of paired organs, including the breasts; however, the basis for this laterality is unknown. Here, we show that despite their morphologic symmetry, left versus right mammary glands in wild-type mice have baseline differences in gene expression that are L-R independently regulated during pubertal development, including genes that regulate luminal progenitor cell renewal, luminal cell differentiation, mammary tumorigenesis, tamoxifen sensitivity and chemotherapeutic resistance. In MMTV-cNeu(Tg/Tg) mice, which model HER2/Neu-amplified breast cancer, baseline L-R differences in mammary gene expression are amplified, sustained or inverted in a gene-specific manner and the mammary ductal epithelium undergoes L-R asymmetric growth and patterning. Comparative genomic analysis of mouse L-R mammary gene expression profiles with gene expression profiles of human breast tumors revealed significant linkage between right-sided gene expression and decreased breast cancer patient survival. Collectively, these findings are the first to demonstrate that mammary glands are lateralized organs, and, moreover, that mammary glands have L-R differential susceptibility to HER2/Neu oncogene-mediated effects on ductal epithelial growth and differentiation. We propose that intrinsic molecular laterality may have a role in L-R asymmetric breast tumor incidence and, furthermore, that interplay between the L-R molecular landscape and oncogene activity may contribute to the differential disease progression and patient outcome that are associated with tumor situs.
authors.affiliation: Department of Regenerative Medicine and Cell Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Robichaux
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Hamilton, ON, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Fuseler
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Hamilton, ON, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Hassell
authors.affiliation: 1] Department of Regenerative Medicine and Cell Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA [2] Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA [3] Program In Women's and Gender Studies, College of Arts and Sciences, University of South Carolina, Columbia, SC, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Ramsdell
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D005260:Female; D015870:Gene Expression; D006801:Humans; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D042361:Mammary Glands, Human / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D015398:Signal Transduction