Clinical Implications of Chromosomal Instability (CIN) and Kinetochore Abnormalities in Breast Cancers.

Genetic instability is a defining property of cancer cells and is the basis of various lesions including point mutations, copy number alterations and translocations. Chromosomal instability (CIN) is part of the genetic instability of cancer and consists of copy number alterations in whole or parts of cancer cell chromosomes. CIN is observed in differing degrees in most cancers. In breast cancer, CIN is commonly part of the genomic landscape of the disease and has a higher incidence in aggressive sub-types. Tumor suppressors that are commonly mutated or disabled in cancer, such as p53 and pRB, play roles in protection against CIN, and as a result, their dysfunction contributes to the establishment or tolerance of CIN. Several structural and regulatory proteins of the centromeres and kinetochore, the complex structure that is responsible for the correct distribution of genetic material in the daughter cells during mitosis, are direct or, mostly, indirect transcription targets of p53 and pRB. Thus, despite the absence of structural defects in genes encoding for centromere and kinetochore components, dysfunction of these tumor suppressors may have profound implications for the correct function of the mitotic apparatus contributing to CIN. CIN and its prognostic and therapeutic implications in breast cancer are discussed in this article.