Research Grants Awarded
Potential values of CAPC in early detection, treatment, and prevention of breast cancer invasion
Scientific Abstract Background: Cytokeratin-associated protein in cancer (CAPC) is coded by a recently discovered, but not yet fully defined gene. RT-PCR analysis detected a significant elevation of CAPC mRNA in 26 of 33 breast and other cancers. Immunohistochemical studies in a small number of breast tumors showed that nearly all normal and hyperplastic cells completely lacked CAPC expression. Among in situ tumors, CAPC was exclusively or preferentially elevated in cells overlying focally disrupted myoepithelial (ME) cell layers. In tumors with co-existing normal, benign, in situ, and invasive components, the invasive lesion consistently showed the highest number of CAPC positive cells and the strongest CAPC immunostaining. All mitotic tumor cells expressed high level of CAPC, but no CAPC expression was seen in normal mitotic cells. Objective/Hypothesis: This study intends to confirm our previous findings in a lager number of cases, to test two hypotheses:  CAPC expression linearly increases with tumor progression;  CAPC positive cells overlying focal ME cell layer disruptions share the same genetic profile with invasive lesions. Specific Aims and Study Design: The level and frequency of CAPC expression between 200 recurrent and primary tumors, and among components of 300 tumors with co-existing normal, hyperplastic, in situ, and invasive lesions will be statistically compared. The expression status of over 700 genes implicated in tumor invasion, cell cycle control, apoptosis, stem cells, and auto-immunoreactions among CAPC positive cells overlying focally disrupted ME cell layers, adjacent cells within the same tumor, and invasive cancers will be profiled with cDNA arrays. Genes exclusively expressed in CAPC positive cells overlying focally disrupted ME cell layers will be further defined with RT-PCR, in situ hybridization, and sequencing. The outcomes of this study are likely to be consistent with previous findings, further suggesting that CAPC is a tumor specific marker that facilitates or triggers breast tumor invasion. Thus, quantitative assessment of CAPC expression may facilitate early detection of the specific in situ tumors at a greater risk for invasion. The development of corresponding agents to target CAPC might provide a novel approach to disrupt the tumor doubling process, facilitating the treatment of tumors with high mitotic figures.
Lay Abstract The development of breast cancer is believed to be a multi-step process, sequentially progressing from normal, to hyperplastic, to in situ, and to invasive stages. The progression from one stage to the other is believed to be driven by tumor specific proteins, which promote tumor cell growth or prevent tumor cell death. Attempting to identify such proteins that may be used for breast cancer immunotherapies, or for diagnostic markers, we have assessed the profile of a recently discovered protein named as cytokeratin-associated protein in cancer (CAPC). Our studies in a small number of breast tumors showed that the mRNA of this protein was markedly elevated in 26 of 33 breast cancers. Our studies also showed that nearly all the normal and benign tumor cells were devoid of CAPC expression, but over 80% of invasive cancer cells were strongly positive for CAPC. Similarly, most in situ tumors showed no CAPC expression, but most tumor cells overlying focally disrupted tumor capsules (which are early signs of cancer invasion) showed high levels of CAPC expression. No CAPC expression was seen in normal mitotic cells, whereas all mitotic tumor cells were strongly positive for CAPC. Together, our findings suggest that CAPC is closely associated with breast cancer progression and invasion. Since over 95% cancer-related death results from invasion-associated illnesses, our proposed study attempts to confirm our findings in a larger number of cases, to test two hypotheses:  CAPC expression promotes tumor progression from the in situ to invasive stage, and  tumor cells overlying focally disrupted capsules are the precursor of invasive lesions. A total of 200 primary and recurrent tumors, and 300 tumors with co-existing normal, benign, in situ, and invasive components will be randomly selected from a large tumor sample pool. The levels and frequencies of CAPC expression between primary and recurrent tumors and among different tissue components will be statistically compared. The expression status of over 700 genes implicated in tumor invasion-related process among CAPC positive tumor cells overlying focally disrupted capsules, adjacent cells within the same tumor, and invasive cancer cells, will be also be compared. If the outcomes of our study are consistent with previous findings, CAPC could be used in clinical screening for early detection and risk assessment. The development of therapeutic agents to target CAPC may provide a new approach for breast cancer treatment.