BREAST CANCER ETIOLOGY, DETECTION, AND TREATMENT

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The human genome contains numerous endogenous retroviral elements, although most appear to be defective. The human endogenous retrovirus type K (HERV-K), however, present at about fifty copies in the genome, appears to be complete. It possesses open reading frames for the usual gag, pol, and env retroviral genes, as well as a central open reading frame which encodes a putative regulatory protein. We have been investigating a possible role of HERV-K in human breast carcinoma based in large part on the significant sequence homology of HERV-K with the mouse mammary tumor virus, which causes mammary cancer in mice. Using novel short-term breast cancer cell strains, we previously examined mRNA expression of HERV-K genes and observed that in some paired samples, derived from human patients, all HERV-K genes were expressed in the culture derived from the tumor cells but not in the culture derived from matched normal adjacent tissue. In addition, some breast tumor cell strains exhibited retroviral reverse transcriptase activity, which could not be attributable to known cellular DNA polymerases, such as DNA polymerase or other contaminating reverse transcriptases from animal retroviruses. Currently we are examining mRNA expression of HERV-K genes in paired tissue samples from breast tumor and normal adjacent tissue by both northern blot and reverse transcriptase-polymerase chain reaction in order to determine if the complete HERV-K retrovirus is expressed in some human breast cancers. In addition, we are exploring DNA methylation patterns in the same paired samples. One mechanism for breast cancer induction could involve altered methylation states, which could lead to expression of HERV-K genes along with adjacent cellular oncogenes. Identification of the adjacent genes could shed light on the mechanism of tumor induction. The nature of the reverse transcriptase activity detected is also under investigation in order to determine if it is encoded by HERV-K. Finally, serologic studies are continuing in order to determine if expression of HERV-K proteins leads to elicitation of HERV-K-specific antibodies in patients with certain types of breast cancer but not in healthy women. Detection of such antibodies could not only link the particular cancer with the endogenous retrovirus, but it might also provide a simple test for initial diagnosis or relapse.