PIs: Jean Latimer
Co-PIs: Stephen Grant and Michael Epperly
Title: Biomarkers of invasiveness using isogenic and progressive human ductal carcinoma in situ cell lines
Description: We have developed a novel tissue engineering system for Human Mammary Epithelial Cells (HMEC), both normal and malignant. This system allows for the long-term (>3 months) establishment of normal primary cultures that begin as 3-dimensional mammospheres. These mammospheres differentiate into complex branching ducts and lobules, i.e. reform the plumbing system of the breast in culture. The ability to form ductal structures from human breast tissue is absolutely unique to our laboratory. Tumor cells lack the ability to form these epithelial architectures. From these robust primary cultures we have generated 2 unprecedented DCIS cell lines from the same white patient¹s breast without the use of viruses or telomerase expression.
Recently we have also created another set of set of DCIS and contralateral cell lines from an Asian woman. The DCIS lines show chromosomal abnormalities consistent with a malignant phenotype (although not as abnormal as MCF7). Our initial goal was to use matched sets of DCIS cell lines to identify biomarkers consistent with early stages of breast oncogenesis by comparing the contralateral cell lines with DCIS cell lines.We have now developed a set of biomarkers from microarray analysis that correlate well with invasiveness potential in these isogenic sets of cell lines. Validation of these biomarkers has been obtained using additional stage I and II cell lines we have also established, with known clinical recurrence patterns in the patients. In aim 2 we will validate the invasiveness of these cell lines by placing all DCIS and isogenically matched contralateral and non-tumor cell lines into transwell chambers and immunocompromised mice. Subcultures of the most motile cells will be analyzed in each case with microarray to validate the markers most associated with a motile and invasive phenotype. Concurrently, we will establish similar matched sets of DCIS cell lines from African American women. In women diagnosed with DCIS 1973-2000, 9.2% were White, 10.2% Black, 7.3% American Indian, 15.0% Asian/Pacific Islander, and 11.5% Other. Black women had a relative risk of mortality of 1.35 compared to white women, while Asian women had a reduced relative risk of 0.74, American Indian women had a RR of 0.95. The results we have obtained on the white and Asian women will be compared with those of the AA women in our study to assess whether DCIS, is associated with a higher risk of invasiveness in AA women. DCIS is one of the most commonly diagnosed forms of breast cancer (BC) because it is visible on mammograms. At the same time it is one of the least understood forms of BC with the likelihood of becoming invasive BC unknown. We have identified biomarkers associated with the early stages of breast oncogenesis using these unique progressive systems. We will further develop a population specific set of invasiveness markers for DCIS to assist in the tailoring of treatments for DCIS in African American women.
Source: Komen for the Cure Agency
Term: 2 years, 5/1/07-4/31/09