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鄄 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/Cnegative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non鄄 cancerous primary breast epithelial cells. Down鄄 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.

C-terminal Src Kinase (Csk)-mediated Phosphorylation of Eukaryotic Elongation Factor 2 (eEF2) Promotes Proteolytic Cleavage and Nuclear Translocation of eEF2

“…Although the exact molecular mechanism by which the small fragments induce nuclear instability needs further investigation, one possibility is that the small fragments interfere with the function of nuclear lamins, as we observed irregular shapes of nuclear membrane in cells expressing the small fragments. It is known that nuclear lamins are important in maintaining genome stability (47)(48)(49).…”

Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli

“…8 For example, deregulation of lamin A/C expression occurs in many human tumors. [9][10][11][12][13] We reported recently that the expression of SUN1, SUN2, nesprin-2, and lamin A/C are down-regulated in breast cancer tissues, 14 suggesting an association of the LINC complex and nuclear lamina components with abnormal nuclear shape and structure. However, the biological consequences of the loss of these major nuclear structural molecules in cancer cells remain to be investigated.…”

New biological research and understanding of Papanicolaou's test

“…3 Early reports indicate that activation of oncogenes or inactivation of tumor suppressor genes leads to nuclear morphological changes. [4][5][6] More recent studies suggest that loss or reduction of structural proteins of the nuclear envelope and lamina, such as Lamin A/C, [7][8][9] Emerin, 10 and the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex components such as nesprins, 11 may explain the nuclear shape changes in cancer cells. In a study of ovarian cancer, it was estimated that 55% of ovarian carcinomas lack Lamin A/ C expression, and about 30% of tumors show heterogeneous staining in the cancer cell population.…”