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Loss of the Expression of the Tumor Suppressor Gene ARHI Is Associated with Progression of Breast Cancer¹

Departments of Experimental Therapeutics [L. W., R. Z. L., J. Y., Z. L., A. N., R. C. B., Y. Y.], Clinical Cancer Prevention [A. H., S. M. L.], and Pathology [J. L., A. A. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose: Ductal carcinoma in situ (DCIS) is a preinvasive-stage breast carcinogenesis that accounts for 2025% of mammographically detected breast cancers. A significant fraction of untreated DCIS will evolve into invasive cancer. ras homologue I (ARHI) is an imprinted tumor suppressor gene that is expressed in normal breast epithelial cells but absent or down-regulated in breast cancer cells. This study investigated the relationship of ARHI expression to the progression of breast cancer.

Experimental Design: We analyzed ARHI expression in DCIS, invasive breast carcinoma, and adjacent normal breast epithelium from 64 formalin-fixed, paraffin-embedded DCIS specimens by both immunohistochemistry and in situ hybridization. We also analyzed the correlation between ARHI expression and progression of breast cancer, as well as the correlation of ARHI expression and cyclin D1 and p21^WAF1/CIP1 expression in DCIS.

Results: Normal breast epithelium was found in all of the specimens and invasive breast carcinoma was found in 23 specimens. ARHI mRNA and protein were detected in all of the normal breast epithelia. ARHI expression was detected mainly in cytoplasm and rarely present in the nucleus. By histochemical analysis, ARHI expression was down-regulated in 41% (26 of 64) of DCIS and 70% (16 of 23) of invasive carcinomas comparing the specimens with adjacent normal breast epithelium. When DCIS and invasive cancer were present in the same sample, ARHI was further down-regulated in 26% (6 of 23) of invasive carcinoma. In four cases [4 (17%) of 23] of invasive carcinoma, ARHI protein expression was totally lost. Consistent results were obtained with an in situ hybridization assay for ARHI at the mRNA level. Higher levels of expression of cyclin D1 and p21^WAF1/CIP1 were observed in DCIS than in the adjacent epithelia. The expression of cyclin D1 and p21^WAF1/CIP1 was inversely correlated with that of ARHI.

Conclusions: Our results indicate that ARHI expression is markedly down-regulated in DCIS, and a further decrease in ARHI expression is associated with progression of breast cancer.

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