Molecules that are aberrantly expressed in tumors often elicit antibody (Ab) responses in cancer patients. By generating anti-tumor Abs, the immune system amplifies a 'signal' indicating a tumor's presence. Therefore, assaying serum Abs to tumor antigens is a potentially powerful approach for early cancer detection. Our long term goal is to identify molecules that are associated with early developmental events in epithelial ovarian cancers (EOC) and to develop assays that detect serum Abs to these molecules as a means of early diagnosis. This objective is critical for reducing the morbidity and mortality caused by EOC, because the majority of patients are diagnosed with late-stage disease that is rarely cured by current therapies. EOCs are thought to arise from the ovarian surface epithelium (OSE), and often bear striking architectural resemblance to the specialized epithelia of the reproductive tract that derive from the mullerian ducts. Mullerian-like features have also been observed in overtly normal ovaries of women with a family history of EOC who are at increased risk of developing the disease. These observations indicate that an early step of epithelial ovarian neoplasia involves inappropriate expression of molecules that normally regulate mullerian differentiation. We have found that the homeobox gene HOXA7 is expressed in normal mtillerian duct-derived epithelia but not in normal OSE, and that aberrant expression of HOXA 7 in OSE cells promotes their acquisition of mullerian-like features. Furthermore, HOXA7 protein was found to be expressed in EOCs and to elicit a specific Ab response in patients but not in healthy women. Homeobox genes are 'master regulators' of differentiation. Studies in mouse models indicate that mullerian duct development is controlled by various homeobox genes including hoxa9, hoxa10, hoxa11, emx2, pax-2 and msx1. We hypothesize that 1) homeobox genes that regulate mullerian duct development are aberrantly expressed in EOCs and in overtly normal ovaries of women with a family history of EOC, and 2) women with EOC and those with a family history of EOC generate serum Abs to proteins encoded by these homeobox genes. Specifically we aim to 1) examine expression of homeobox genes that regulate mullerian duct development in tissue microarrays of specimens of EOCs and ovarian tissues of women with a family history of EOC and 2) develop enzyme-linked immunosorbent assays that detect Abs to products of these homeobox genes in sera of EOC patients and of women with a family history of EOC. ? ? ?
| Cheng, Wenjun; Liu, Jinsong; Yoshida, Hiroyuki et al. (2005) Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nat Med 11:531-7 |
| Naora, Honami (2005) Developmental patterning in the wrong context: the paradox of epithelial ovarian cancers. Cell Cycle 4:1033-5 |
| Samuel, Shaija; Naora, Honami (2005) Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer 41:2428-37 |
