Robichaux J P, Hallett R M, Fuseler J W, Hassell J A, Ramsdell A F
Department of Regenerative Medicine and Cell Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Department of Biochemistry and Biomedical Sciences, Centre for Functional Genomics, McMaster University, Hamilton, ON, Canada.
Oncogene. 2015 Apr 9;34(15):2003-10. doi: 10.1038/onc.2014.149. Epub 2014 Jun 9.
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.
包括乳腺在内的成对器官的癌症在肿瘤发生率和疾病转归方面存在显著的左右差异；然而，这种左右差异的基础尚不清楚。在这里，我们表明，尽管野生型小鼠的左右乳腺在形态上对称，但在青春期发育过程中，它们在基因表达上存在基线差异，这些差异是由左右独立调控的，包括调节管腔祖细胞更新、管腔细胞分化、乳腺肿瘤发生、他莫昔芬敏感性和化疗耐药性的基因。在模拟HER2/Neu扩增型乳腺癌的MMTV-cNeu(Tg/Tg)小鼠中，乳腺基因表达的基线左右差异以基因特异性方式被放大、持续或反转，并且乳腺导管上皮经历左右不对称生长和模式形成。对小鼠左右乳腺基因表达谱与人类乳腺肿瘤基因表达谱的比较基因组分析揭示了右侧基因表达与乳腺癌患者生存率降低之间的显著关联。总体而言，这些发现首次证明乳腺是左右不对称的器官，此外，乳腺对HER2/Neu癌基因介导的导管上皮生长和分化作用具有左右差异敏感性。我们提出，内在的分子左右不对称性可能在左右不对称乳腺肿瘤发生率中起作用，此外，左右分子格局与癌基因活性之间的相互作用可能导致与肿瘤位置相关的疾病进展差异和患者转归。
