A novel mechanism for the chemoprotection by 3,3-diindolylmethane (DIM) and genistein for breast and ovarian cancers Free

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Cruciferous vegetables are thought to be protective for numerous types of cancer. 3,3’-diindolylmethane (DIM) is an acid-catalyzed product generated in the consumption of cruciferous vegetables. Genistein represents a major isoflavone in soy, found at concentrations up to 1.5 mg/ml soy product.Both compounds appear to be chemoprotective; they have been found to reduce the incidence of spontaneous- and carcinogen-induced tumors in rodents, including those of the breast. Both compounds are being pursued as potential chemopreventative and chemotherapeutic agents for breast cancer. The CXCR4/CXCL12 axis is known to play a central role in the metastasis of breast cancer and is also thought to play a role in the development of ovarian cancer. Organs to which these cancers metastasize secrete CXCL12 which binds to CXCR4 expressed on the surface of primary cancer cells. This subsequently stimulates the invasive properties of the cancer cells as well as attracts them to the organ sites of metastases. Interestingly, CXCL12 is also expressed in primary breast and ovarian cancer cells and appears to stimulate proliferation through an autocrine mechanism. We have found that DIM and genistein down-regulate CXCR4 in the ER+ breast cancer cell line, MCF-7, the ER-, metastatic breast cancer cell line, MB-MDA-231, and the ER+, invasive ovarian cancer cell line, BG-1. We also show that DIM down-regulates CXCL12 in MCF-7 and BG-1 cells. In addition, we demonstrate that the potential of MB-MDA-231 and BG-1 cells for chemotaxis and invasion is inhibited by DIM and genistein. As the CXCR4/CXCL12 axis is thought to play a role in the development of 23+ different types of cancers, we have identified numerous other cancer cell lines in which CXCR4 and CXCL12 are modulated upon phytochemical treatment. Finally, we show that treatment with DIM and genistein inhibits the inductive effects of hypoxia on CXCR4 and of estradiol on CXCL12. Our data suggest that one mechanism whereby DIM and genistein protect against breast and ovarian cancers is through the repression of CXCL12 and/or CXCR4, thereby lowering the invasive and metastatic potential of these cells.