Breast cancer is a leading cause of death in women. While the pathogenesis of breast cancer is unclear, transformation of normal breast epithelium to a malignant phenotype may be the result of genetic factors, especially in women under 30. Miki, et al., Science, 266: 66-71 (1994). However, it is likely that other, non-genetic factors also have a significant effect on the etiology of the disease. Regardless of its origin, breast cancer morbidity increases significantly if a lesion is not detected early in its progression. Thus, considerable effort has focused on the elucidation of early cellular events surrounding transformation in breast tissue. Such effort has led to the identification of several potential breast cancer markers. For example, alleles of the BRCA1 and BRCA2 genes have been linked to hereditary and early-onset breast cancer. Wooster, et al., Science, 265: 2088-2090 (1994). The wild-type BRCA1 allele encodes a tumor supressor protein. Deletions and/or other alterations in that allele have been linked to transformation of breast epithelium. Accordingly, detection of mutated BRCA1 alleles or their gene products has been proposed as a means for detecting breast, as well as ovarian, cancers. Miki, et al., supra. However, BRCA1 is limited as a cancer marker because BRCA1 mutations fail to account for the majority of breast cancers. Ford, et al., British J. Cancer, 72: 805-812 (1995). Similarly, the BRCA2 gene, which has been linked to forms of hereditary breast cancer, accounts for only a small portion of total breast cancer cases. Ford, et al., supra.
Several other genes have been linked to breast cancer and may serve as markers for the disease, either directly or via their gene products. Such potential markers include the TP53 gene and its gene product, the p53 tumor supressor protein. Malkin, et al., Science, 250: 1233-1238 (1990). The loss of heterozygosity in genes such as the ataxia telangiectasia gene has also been linked to a high risk of developing breast cancer. Swift, et al., N. Engl. J. Med., 325: 1831-1836 (1991). A problem associated with many of the markers proposed to date is that the oncogenic phenotype is often the result of a gene deletion, thus requiring detection of the absence of the wild-type form as a predictor of transformation.
Of interest to the present invention are reports that the protein content of the nuclear matrix in breast epithelia may provide a marker of cellular growth and gene expression in those cells. Khanuja, et al., Cancer Res., 53: 3394-3398 (1993). The nuclear matrix forms the superstructure of the cell nucleus and comprises multiple protein components that are not fully characterized. The nuclear matrix also provides the structural and functional organization of DNA. For example, the nuclear matrix allows DNA to form loop domains. Portions of DNA in such loop domains have been identified as regions comprising actively-transcribing genes. Ciejek, et al., Nature, 306: 607-609 (1982). Moreover, the organization of the nuclear matrix appears to be tissue-specific and has been associated with so-called transformation proteins in cancer cells. Getzenberg, et al., Cancer Res., 51: 6514-6520 (1991); Stuurman, et al., J. Biol. Chem., 265: 5460-5465 (1990).
Proteins and steroid hormones thought to be involved in transformation are associated with the nuclear matrix in certain cancer cells. Getzenberg, et al., Endocrinol. Rev., 11: 399-417 (1990). It has been suggested that changes in the composition or organization of nuclear matrix proteins may be useful as markers of growth and gene expression in breast tissue. Khanuja, et al., Cancer Res., 53: 3394-3398 (1994). However, Khanuja did not identify any specific proteins for use as cancer markers.
There is, therefore, a need in the art for specific, reliable markers that are differentially expressed in normal and transformed breast tissue and that may be useful in the diagnosis of breast cancer or in the prediction of its onset. Such markers and methods for their use are provided herein.