Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer  

作　　者：Callinice D. Capo-chichi Kathy Q. Cai Jennifer Smedberg Parvin Ganjei-Azar Andrew K. Godwin Xiang-Xi Xu 

机构地区：[1]Sylvester Comprehensive Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA. [2]Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. [3]Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA [4]Department of Pathology,University of Kansas Medical Center, Kansas City, KS 66160, USA. [5]Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. [6]Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami, FL 33136, USA

出　　处：《Chinese Journal of Cancer》2011年第6期415-425,共11页

基　　金：supported by funds from concept awards BC097189 and BC076832 from Department of Defense(USA);Grants R01CA095071,R01CA099471,and CA79716to Xiang-Xi Xu from NCI

摘　　要：Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,the molecular basis for the link between nuclear deformation and malignancy has not been determined.Another hallmark of human cancer is aneuploidy;however,the causes and consequences of aneuploidy are unanswered and are hotly contested topics.We found that nuclear lamina proteins lamin A/C are absent in a significant fraction(38%) of human breast cancer tissues.Even in lamin A/C-positive breast cancer,lamin A/C expression is heterogeneous or aberrant(such as non-nuclear distribution) in the population of tumor cells,as determined by immunohistology and immunofluorescence microscopy.In most breast cancer cell lines,a significant fraction of the lamin A/C-negative population was observed.To determine the consequences of the loss of lamin A/C,we suppressed their expression by shRNA in noncancerous primary breast epithelial cells.Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation,resembling that of cancer cells,as observed by immunofluorescence microscopy.The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization.We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.Through advances in technology, the genetic basis of cancer has been investigated at the genomic level, and many fundamental questions have begun to be addressed. Among several key unresolved questions in cancer biology, the molecular basis for the link between nuclear deformation and malignancy has not been determined. Another hallmark of human cancer is aneuploidy; however, the causes and consequences of aneuploidy are unanswered and are hotly contested topics. We found that nuclear lamina proteins lamin A/C are absent in a significant fraction （38%） of human breast cancer tissues. Even in lamin A/C-positive breast cancer, lamin A/C expression is heterogeneous or aberrant （such as non- nuclear distribution） in the population of tumor cells, as determined by immunohistology and immunofluorescence microscopy. In most breast cancer cell lines, a significant fraction of the lamin A/C- negative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non-cancerous primary breast epithelial cells. Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation, resembling that of cancer cells, as observed by immunofluorescence microscopy. The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization. We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.

关 键 词：核纤层蛋白 乳腺癌 蛋白表达 损失 核被膜 乳腺上皮细胞 非整倍体 整性 

分 类 号：R737.9[医药卫生—肿瘤]