Development of chemotherapies for hormone-dependent breast and prostate cancers.

摘要

Cancer is a leading cause of human mortality worldwide, and is expected to soon become the overall leading cause of death in the United States. Some cancers are hormone-related, including the sex-specific cancers of the breast (predominantly in women) and prostate (in men). In both cases, early stage tumors are responsive to inhibitory endocrine-based therapies. However, both cancers progress to hormone-nonresponsive states and this is in part due to altered properties of the primary nuclear hormone receptor signaling pathway (estrogen receptor [ER] in breast; androgen receptor [AR] in prostate). Other nuclear receptors are thus being investigated as therapeutic targets due to their crosstalk with hormone receptor pathways and these include the aryl hydrocarbon receptor (AhR), peroxisome proliferator activated receptor gamma (PPARgamma), retinoic acid receptor and retinoid X receptor (RAR/RXR), and vitamin D receptor (VDR). Previous studies have demonstrated that the AhR mediates chemoprotective, antiestrogenic, and tumoristatic effects in experimental models, and relatively non-toxic selective aryl hydrocarbon receptor modulators (SAhRMs) have been developed. Studies in this dissertation have investigated the therapeutic properties of a new class of compounds related to the SAhRM 3,3'-diindolylmethane (DIM) in models of breast cancer. Additionally, the potential therapeutic role of the AhR in human prostate cancer cells has been investigated. Several ring- and methylene-substituted DIMs exhibited antiestrogenic and tumoristatic activities in breast cancer cells and in carcinogen-induced rat mammary tumors. At least some of the methylene-substituted DIMs act through PPARgamma. The AhR is expressed in LNCaP and 22Rv1 prostate cancer cells and AhR agonists inhibit cell growth and AR-induced transactivation through pathways independent of androgen receptor downregulation.