A Novel HOX Gene Target in Breast Cancer

George Washington University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): Breast cancer is the leading cause of death among American women who are 35 to 55 years of age. We have cloned a novel human homeobox gene called BP1 which is a potential target for therapy of breast cancer. In tumors from 15 patients with newly diagnosed breast cancer, we found that 13 of the 15 (87%) expressed high levels of BP1 mRNA, whereas BP1 mRNA was undetectable in the remaining 13%. In contrast, BP1 was expressed (at a very low level) in only one of six normal breast tissues. BP1 expression was seen in 100% of the high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative cancers, but in only 33% of ER positive, PR positive breast cancers. Interestingly, BP1 mRNA levels were also found to be high in breast cancer cell lines which are known to be tumorigenic. In this application, we will test the hypothesis that BP1 is a new therapeutic target in breast cancer by analyzing additional tumors and using molecular techniques. Currently we are measuring BP1 in breast tumors by RT-PCR. In this application, immunohistochemical analysis will be developed to facilitate analysis of BP1 expression in histological sections. Of relevance to this grant, previous molecular studies in leukemia suggest that BP1 expression is transforming and is required for survival of a leukemia cell line. If BP1 is part of an anti-apoptotic pathway, its expression may be important in breast cancer cells as well. Stable breast cancer cell lines overexpressing BP1 will be established to determine whether BP1 expression is transforming in vitro. Analysis of a gene array using these cell lines will help to identify genes which may be targets of BP1 and pathways in which it is involved. To determine whether decreasing BP1 levels leads to growth inhibition or apoptosis, BP1 expression will be reduced in breast cancer cell lines using genetic and pharmacological methods. This study will therefore combine clinical and genetic approaches to determine the importance of BP1 expression in breast cancer.