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Abstract
Breast cancer occur both in hereditary and sporadic forms, and the later one comprises an overwhelming majority of breast cancer cases among women. Numerical and structural alterations involving chromosome 8, with loss of short arm (8p) and gain of long arm (8q), are frequently observed in breast cancer cells and tissues. In this study, we show that most of the human breast tumor cell lines examined display an over representation of 8q24, a chromosomal locus RecQL4 is regionally mapped to, and consequently, a markedly elevated level of RecQL4 expression. An increased RecQL4 mRNA level was also observed in a majority of clinical breast tumor samples (38/43) examined. shRNA-mediated RecQL4 suppression in MDA-MB453 breast cancer cells not only significantly inhibit the in vitro clonogenic survival and in vivo tumorigenicity. Further studies demonstrate that RecQL4 physically interacts with a major survival factor-survivin and its protein level affects survivin expression. Although loss of RecQL4 function due to gene mutations causally linked to occurrence of human RTS with features of premature aging and cancer predisposition, our studies provide the evidence that overexpression of RecQL4 due to gene amplification play a critical role in human breast tumor progression.
Highlights
Breast cancer is the most leading cause of cancer related deaths among women [1]
To determine the alterations involving the loss of chromosome 8p and gain of 8q, FISH using chromosome 8 specific multicolor BAND probe was performed on the metaphase spreads of normal mammary epithelial cells (HMEC) and different breast tumor cell lines
Over representation of 8q and under representation of 8p was most evident in MDA-MB453 breast cancer cell line that showed 6 copies of chromosome 8q including a pair of isochromosomes formed by the fusion of two chromosome 8qarms
Summary
Despite advances in endocrine therapy and novel targeted agents, metastatic breast cancer still remains an incurable disease largely because of genetic complexity of this disease, which confers resistance to many treatment modalities [2,3] Breast cancer occurs both in sporadic and hereditary forms. Amplification involving long arms of chromosome 8 has been frequently reported in multiple tumors such as osteosarcoma, prostate cancer, pancreatic cancer, cervical cancer, B-cell acute lymphoblastic leukemia and sacrococcygeal teratoma [7,8,9,10,11,12] These findings suggest that the structural alterations of chromosome 8 may play a causal role in the process of tumor progression. Identification and functional characterization of potential genes responsible for breast tumorigenesis may lead to new therapeutic strategies for effective clinical management of breast cancer
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