The R-enantiomer of ketorolac delays mammary tumor development in mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) mice

Epidemiologic studies report improved breast cancer survival in women receiving ketorolac (Toradol®) for post-operative pain relief compared to other analgesics. Ketorolac is a racemic drug. The S-enantiomer inhibits cyclooxygenases; R-ketorolac is a selective inhibitor of the small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), which are signaling molecules up-regulated during breast cancer progression and metastasis. our goal was to determine whether R-ketorolac altered breast cancer development in the mouse mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) model. Mice were administered ketorolac orally at 1 mg/kg twice daily to approximate the typical human dose. Mammary glands were analyzed for tumor number and immunohistochemical markers of proliferation and differentiation. R-ketorolac treatment significantly reduced mammary epithelial proliferation, based on Ki67 staining, and suppressed tumor development. Proliferative mammary epithelium from R-ketorolac–treated mice displayed greater differentiation, based on significantly higher total E-cadherin and decreased keratin 5 staining, than epithelium of placebo-treated mice. No differences were detected in estrogen receptor, progesterone receptor, β-catenin, or vimentin expression between placebo and R-ketorolac treatment groups. These findings indicate that R-ketorolac treatment slows breast cancer progression in an aggressive model of breast cancer. R-ketorolac may thus represent a novel therapeutic approach for breast cancer prevention or treatment based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor.

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Amanda S. Peretti, Dayna Dominguez, Martha M. Grimes, Helen J. Hathaway, Eric R. Prossnitz, Melanie R. Rivera, Angela Wandinger-Ness, Donna F. Kusewitt, & Laurie G. Hudson

The American Journal of Pathology, 2017

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