Cux Transcription Factor as a Diagnostic and Prognostic Tool in Breast Cancer and Other Malignancies

Higher expression of CDP/Cux (CCAAT-displacement protein/cut homeobox) was reported in various human cancers and is often associated with more aggressive disease. CDP/Cux is a transcription factor that plays a role in cellular proliferation and, in specific contexts, in cell migration and invasion. CDP/Cux stimulates cell proliferation by accelerating entry into S phase. Interestingly, it is not the full-length p200 CDP/Cux protein that is responsible for this activity but shorter isoforms. One isoform called p110 is generated by proteolytic processing. In normal cells, this processing event is tightly regulated, however, in many cancer cells, it becomes constitutive. In some breast cancers, another short isoform called p75 was found to be aberrantly expressed from an alternative mRNA. In invasive tumors a significant association was established between higher expression of p75 and a diffuse infiltrative growth pattern (n=41, p=0.0137). Transgenic mouse models were generated to assess the oncogenic potential of the 3 CDP/Cux isoforms: p200, p110 and p75. While p200 did not increase the susceptibility of mice to cancer, both the p75 and p110 isoforms caused malignancies. Although the transgenes were targeted to the mammary gland, tumors were found not only in the mammary gland but also in many other organs including the ovary, uterus, liver and spleen. Increased expression of short CDP/Cux isoform appear to contribute to tumor development and progression.

The prognostic factors currently available in breast cancer leave much to be desired. Only 70% of patients with “good prognosis breast cancer” are actually cured by surgery alone while 30 % of them will see their cancers recur. Moreover, the establishment of lymph node status, which is one of the most useful prognostic factors in breast cancer, is not without complications. To name but one, lymphedema, a potentially devastating complication of axillary node dissection, may occur in up to 24% of patients. The demonstrated roles of CUX1 in cell proliferation, migration and invasion are consistent with the notion that aberrant CUX1 activity may contribute to tumor initiation and/or progression. Therefore the detection of short isoforms of CUX1 in tumor tissue provide novel prognostic indicators of severety for breast cancer and other malignancies.