CXCR4 and CXCL12 down-regulation: A novel mechanism for the chemoprotection of 3,3′-diindolylmethane for breast and ovarian cancers

• Published in: Cancer letters 2008-06, Vol.265 (1), p.113-123
• Main Authors: Hsu, Erin L, Chen, Natalie, Westbrook, Aya, Wang, Feng, Zhang, Ruixue, Taylor, Robert T, Hankinson, Oliver
• Format: Article
• Language: English
• Subjects: 3,3′-Diindolylmethane; Animals; Anticarcinogenic Agents - pharmacology; Breast cancer; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer metastasis; Cattle; Cell Hypoxia; Cell Line, Tumor; Chemokine CXCL12 - biosynthesis; Chemotaxis - drug effects; CXCL12; CXCR4; DIM; Down-Regulation; Estradiol - pharmacology; Female; Hematology, Oncology and Palliative Medicine; Humans; Indoles - pharmacology; Medical research; Mortality; Neoplasm Invasiveness; Ovarian cancer; Ovarian Neoplasms - pathology; Ovarian Neoplasms - prevention & control; Receptors, CXCR4 - biosynthesis; Serum Albumin, Bovine - pharmacology
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.02.033

Abstract Cruciferous vegetables are thought to protect against numerous types of cancer. 3,3′-Diindolylmethane (DIM) is an acid-catalyzed product generated during the consumption of cruciferous vegetables and appears to be chemoprotective for breast cancer. The interaction between the chemokine receptor, CXCR4, and its unique ligand, CXCL12, is known to mediate the progression and metastasis of breast and other cancers. Organs to which these cancers metastasize secrete CXCL12, which binds to CXCR4 expressed on the surface of primary cancer cells. This process subsequently stimulates the invasive properties of the cancer cells and attracts them to the preferred organ sites of metastases. We have found that DIM down-regulates both CXCR4 and CXCL12 in MCF-7 and MDA-MB-231 breast cancer cells as well as in BG-1 ovarian cancer cells at the transcriptional level and in an estrogen-independent manner. We demonstrate that the potential of MDA-MB-231 and BG-1 cells for chemotaxis and invasion towards CXCL12, but not towards IL-6 or fetal bovine serum, respectively, is inhibited by DIM. Furthermore, we show that DIM down-regulates CXCR4 under hypoxia and CXCL12 under estradiol-inducing conditions. Our data suggest that one mechanism whereby DIM protects against breast, ovarian, and possibly other cancers is through the repression of CXCR4 and/or CXCL12, thereby lowering the invasive and metastatic potential of these cells.