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

Abstract

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.

Nuclear assembly as a target for anti-cancer therapies

“…In conclusion, altered lamin expression or localization and disrupted stoichiometry between A- and B-type lamins can change the elastic properties of the NE, 16 which renders it unable to withstand cytoskeleton- 47 , 48 and chromosome-based 49 , 50 forces and leads to misshapen nuclei. Consistently, downregulation of lamin A/C in non-cancer primary breast epithelial cells results in nuclear alterations similar to those observed in breast cancer cell 38 . Moreover, mutations in LMNA and other genes encoding for proteins of nuclear lamina results in heritable diseases called laminopathies, 51 which are also characterized by fragile 52 and multi-lobulated nuclear shape 53 .…”

“…For example, in small cell lung cancer (SCLC) cells A-type lamins are either not or only weakly expressed, while in non-SCLC cells they are normally expressed but frequently mislocalized in the cytoplasm 32 - 34 . In colon cancers, 35 gastric cancers, 36 , 37 breast cancers, 38 , 39 and diffuse large B-cell lymphomas, 40 the expression of A-type lamins is also strongly reduced, and this feature correlates with increased disease recurrence and poor patient prognosis. Consequently, the nuclei of these cancer types are often fragile and lobulated, and in breast cancer cells, they were shown to contain massive NE membrane invaginations 27 , 28 (Fig.…”

Nuclear envelope structural defect underlies the main cause of aneuploidy in ovarian carcinogenesis

“…Loss or reduction of lamin A/C expression is often found in cancer cells [47], including leukemia [48, 49], colon [50], prostate [29], lung [51], breast [52], and gastric cancers [53, 54]. Our earlier study also found that lamin A/C expression is lost in about 60 % of serous ovarian carcinomas, in which the mRNA is often present despite the loss of protein [55].…”

The Emerging Role of Cytoskeletal Proteins as Reliable Biomarkers

“…Reduced expression of lamin in tumor cells compared to normal has been reported by some in refs. [], whereas increased expression has been reported by others. It is clear that lamins have multiple functions, which range from providing structure to the nucleus to being associated with transmembrane proteins and regulating signaling.…”