Abstract
During cell division, chromosome segregation is facilitated by the mitotic checkpoint, or spindle assembly checkpoint (SAC), which ensures correct kinetochore-microtubule attachments and prevents premature sister-chromatid separation. It is well established that misexpression of SAC components on the outer kinetochores promotes chromosome instability (CIN) and tumorigenesis. Here, we study the expression of CENP-I, a key component of the HIKM complex at the inner kinetochores, in breast cancer, including ductal, lobular, medullary and male breast carcinomas. CENPI mRNA and protein levels are significantly elevated in estrogen receptor-positive (ER+) but not in estrogen receptor-negative (ER-) breast carcinoma. Well-established prognostic tests indicate that CENPI overexpression constitutes a powerful independent marker for poor patient prognosis and survival in ER+ breast cancer. We further demonstrate that CENPI is an E2F target gene. Consistently, it is overexpressed in RB1-deficient breast cancers. However, CENP-I overexpression is not purely due to cell cycle-associated expression. In ER+ breast cancer cells, CENP-I overexpression promotes CIN, especially chromosome gains. In addition, in ER+ breast carcinomas the degree of CENPI overexpression is proportional to the level of aneuploidy and CENPI overexpression is one of the strongest markers for CIN identified to date. Our results indicate that overexpression of the inner kinetochore protein CENP-I promotes CIN and forecasts poor prognosis for ER+ breast cancer patients. These observations provide novel mechanistic insights and have important implications for breast cancer diagnostics and potentially therapeutic targeting.
Highlights
Checkpoints are essential in cell cycle regulation
While it is unclear whether CENPI levels are typically abnormal in breast cancer stromal cells, 20 out of 20 studies indicate that breast carcinoma intrinsic CENPI mRNA levels are significantly increased (Figure 1A)
We find that CENPI overexpression is a marker for poor patient outcome in breast cancer
Summary
Checkpoints are essential in cell cycle regulation. The mitotic checkpoint, or spindle assembly checkpoint (SAC), ensures that chromosomes segregate accurately during mitosis. Kinetochores establish a platform for microtubule attachments, which are critical www.impactjournals.com/oncotarget for faithful chromosome segregation These interactions occur at the outer kinetochore, which is the primary site of SAC signaling. A large body of research has focused on understanding the molecular mechanisms of SAC function, in particular studying key signaling components and effectors such as MAD1, MAD2, BUB1, BUBR1, TTK, CDC20 and APC/C While these SAC proteins are important in controlling chromosome segregation [8], recent studies imply that various other inner and outer kinetochore components are required for the correct establishment of microtubule-kinetochore interactions and SAC function, thereby indirectly controlling chromosome segregation. Individual HIKM components may not be directly involved in microtubulekinetochore interactions, they are essential for their efficient establishment and SAC function [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
