Retrospective validation of putative breast cancer predictive molecular markers

Howard University, Washington DC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Although there is a slight decline in the deaths from invasive breast cancer in recent years, it continues to be the most diagnosed cancer and the second leading cause of cancer deaths for women in the US. We can expect a significant reduction in the death rate if the cancer is detected and treated at the precancerous stage. However, there are no known markers to detect a precancerous stage or predict which precancerous lesions will develop into IBC. We recently identified over 300 putative breast cancer predictive molecular markers by global gene expression analysis of precancerous lesions from patients with and without the history of cancer. However, it is not known which of the 300 putative markers could be applied for detecting a 'True Precancerous Stage' and predicting cancer development unless they are validated. Our long range goal is to reduce mortality rate with breast cancer, by detecting at the precancerous stage. The objective of this application is to establish that at least three of the putative markers could be applied as breast cancer predictive markers. Our rationale that the putative markers that were identified by us could be applied as predictive markers was based on our preliminary data obtained using limited number of archival precancerous lesions. Our data suggested that three of the putative markers were highly expressed in precancerous tissues from patients who later developed cancer and were absent in the control group. We will accomplish the objective of this application by pursuing two specific aims: 1) Establish that elevated expression of at least three putative markers is associated with subsequent development of cancer using archival precancerous tissues and by immunohistochemistry, 2) Establish that the validated markers could be detected at their mRNA levels in mostly atypical cells and a small percentage of benign cells obtained by ductal lavage collection procedure by RT real-time PCR. The rationale for the proposed work is that 1) once we establish that elevated expression of the predictive markers is associated with subsequent development of breast cancer, that information could be used for screening precancerous lesions and identifying patients with lesions that may develop into cancer, and 2) the validated markers could be used for screening women with no lesions using samples of ductal cells obtained by procedures such as ductal lavage collection and identifying those at very high risk of cancer development. The proposed work is innovative, because predictions on cancer development will be based on the expression of a group of molecular markers instead of histological diagnosis of precancerous lesions. It capitalizes on the putative breast cancer markers identified by us which to our knowledge not done by any one else. It is our expectation that elevated expression of the putative molecular markers will predict cancer development and those molecules could be detected in ductal lavage by RT real-time PCR. The outcomes will be significant, because it is expected that the new knowledge could be applied to detect cancer at the precancerous stage before mammographically detectable or palpable tumor are formed. Detection and treatment at the precancerous stage will have a major impact in reducing the deaths from cancer, simultaneously cutting down the health care cost. The current project is to identify markers that detect a pre-cancerous stage and predict development of breast cancer in women who have mammographically detectable benign lesions as well as in women who have no mammographically detectable lesions. Detection at the precancerous stage and treatment could lead to fewer incidences of breast cancer and deaths from it. [unreadable] [unreadable] [unreadable]