11P - Impact of the sterol 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol on tumor-pathological features, prognosis and response to statin treatment...

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Cytotoxic agents
Breast Cancer
Therapy
Biological therapy
Presenter Siker Kimbung
Authors S. Kimbung1, C. Chang2, P. Bendahl1, L. Dubois2, W.J. Thompson2, D.P. McDonnell2, S. Borgquist1
  • 1Division Of Oncology And Pathology, Department Of Clinical Sciences, Lund, Lund University, Sweden, SE-221 85 - Lund/SE
  • 2Department Of Pharmacology And Cancer Biology, Duke University School of Medicine, 27710 - NC/US

Abstract

Body

The impact of systemic 27-hydroxycholesterol (27HC) and intra-tumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1 which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and the basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER positive breast cancer seemed limited to women ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and suggest that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. It is implied from these studies that other undetermined serum or tumor factors mediate the anti-proliferative effects of statins in breast cancer.

Clinical trial identification