Abstract
Cancer cells exhibit a variety of features indicative of atypical nuclei. However, the molecular mechanisms underlying these phenomena remain to be elucidated. The linker of nucleoskeleton and cytoskeleton (LINC) complex, a nuclear envelope protein complex consisting mainly of the SUN and nesprin proteins, connects nuclear lamina and cytoskeletal filaments and helps to regulate the size and shape of the nucleus. Using immunohistology, we found that a nuclear lamina component, lamin A/C and all of the investigated LINC complex components, SUN1, SUN2, and nesprin-2, were downregulated in human breast cancer tissues. In the majority of cases, we observed lower expression levels of these analytes in samples' cancerous regions as compared to their cancer-associated noncancerous regions (in cancerous regions, percentage of tissue samples exhibiting low protein expression: lamin A/C, 85% [n = 73]; SUN1, 88% [n = 43]; SUN2, 74% [n = 43]; and nesprin-2, 79% [n = 53]). Statistical analysis showed that the frequencies of recurrence and HER2 expression were negatively correlated with lamin A/C expression (P < 0.05), and intrinsic subtype and ki-67 level were associated with nesprin-2 expression (P < 0.05). In addition, combinatorial analysis using the above four parameters showed that all patients exhibited reduced expression of at least one of four components despite the tumor's pathological classification. Furthermore, several cultured breast cancer cell lines expressed less SUN1, SUN2, nesprin-2 mRNA, and lamin A/C compared to noncancerous mammary gland cells. Together, these results suggest that the strongly reduced expression of LINC complex and nuclear lamina components may play fundamental pathological functions in breast cancer progression.
Highlights
The nuclear architecture provides a framework for organizing and regulating the diverse functional processes within cells
The linker of nucleoskeleton and cytoskeleton (LINC) complex, a multifunctional NE protein assembly that maintains nuclear structure, is composed primarily of two kinds of protein families: nesprin proteins, which are recruited to the outer nuclear membrane, where they interact with the cytoskeleton; SUN proteins, located in the inner nuclear membrane, where they interact with lamins in the nucleoplasm and with nesprin proteins in the perinuclear space [3, 4]
Consistent with a previous result [13], most cases showed that lamin A/C staining was less intense in cancerous regions (Fig. 1, middle column) than in cancer-associated noncancerous regions (Fig. 1, left column), some cases showed normal expression (Fig. 1, right column)
Summary
The nuclear architecture provides a framework for organizing and regulating the diverse functional processes within cells. There are significant differences in nuclear architecture between cancer and normal cells [1, 2]. The LINC (linker of nucleoskeleton and cytoskeleton) complex, a multifunctional NE protein assembly that maintains nuclear structure, is composed primarily of two kinds of protein families: nesprin proteins, which are recruited to the outer nuclear membrane, where they interact with the cytoskeleton; SUN proteins, located in the inner nuclear membrane, where they interact with lamins in the nucleoplasm and with nesprin proteins in the perinuclear space [3, 4]. Lamin proteins, which are intermediate filaments located under the nuclear envelope, are components of nuclear lamina that function as a nuclear skeleton. Each of these proteins is composed of multiple
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