Abstract
PurposeCholesterol lowering statins have been demonstrated to exert anti-tumoral effects on breast cancer by decreasing proliferation as measured by Ki67. The biological mechanisms behind the anti-proliferative effects remain elusive. The aim of this study was to investigate potential statin-induced effects on the central cell cycle regulators cyclin D1 and p27.Experimental designThis phase II window-of-opportunity trial (Trial registration: ClinicalTrials.gov NCT00816244, NIH) included 50 patients with primary invasive breast cancer. High-dose atorvastatin (80 mg/day) was prescribed to patients for two weeks prior to surgery. Paired paraffin embedded pre- and post-statin treatment tumor samples were analyzed using immunohistochemistry for the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and the cell cycle regulators cyclin D1 and p27. Corresponding frozen tumor sample pairs were analyzed for expression of the genes coding for cyclin D1 and p27, CCND1 and CDKN1B, respectively.ResultsForty-two patients completed all study parts, and immunohistochemical evaluation of ER and PR was achievable in 30 tumor pairs, HER2 in 29 tumor pairs, cyclin D1 in 30 tumor pairs and p27 in 33 tumor pairs. The expression of ER, PR and HER2 did not change significantly following atorvastatin treatment. Cyclin D1 expression in terms of nuclear intensity was significantly decreased (P = 0.008) after statin treatment in paired tumor samples. The protein expression of the tumor suppressor p27, evaluated either as the fraction of stained tumor cells or as cytoplasmic intensity, increased significantly (P = 0.03 and P = 0.02, respectively). At the transcriptional level, no significant differences in mRNA expression were detected for cyclin D1 (CCND1) and p27 (CDKN1B). However, CCND1 expression was lower in tumors responding to atorvastatin treatment with a decrease in proliferation although not significantly (P = 0.08).ConclusionsWe have previously reported statin-induced anti-proliferative effects in breast cancer. This study suggests that cell cycle regulatory effects may contribute to these anti-proliferative effects via cyclin D1 and p27.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0486-0) contains supplementary material, which is available to authorized users.
Highlights
Statins, a major class of drugs for treatment of hypercholesterolemia, are widely used due to a notable prevention of cardiovascular disease, and accumulating evidence proposes a promising role of statins in breast cancer [1]
Forty-two patients completed all study parts, and immunohistochemical evaluation of estrogen receptor (ER) and progesterone receptor (PR) was achievable in 30 tumor pairs, human epidermal growth factor receptor 2 (HER2) in tumor pairs, cyclin D1 in tumor pairs and p27 in 33 tumor pairs
No significant differences in mRNA expression were detected for cyclin D1 (CCND1) and p27 (CDKN1B)
Summary
A major class of drugs for treatment of hypercholesterolemia, are widely used due to a notable prevention of cardiovascular disease, and accumulating evidence proposes a promising role of statins in breast cancer [1]. The anti-proliferative effects of statins were confirmed in invasive breast cancer, as reported in a previous publication from the same trial on which this study is based [15]. In both studies, the anti-proliferative effects were described in terms of decreased intra-tumoral levels of Ki67 [14,15]. The CDKs form complexes with their regulatory units, cyclins, thereby activating the CDKs, leading to phosphorylation of the cell cycle regulatory proteins that initiate and regulate progression through the different phases of the cell cycle [19]. The tumor suppressor p27 is frequently deregulated in breast cancer, and reduced p27 expression has been associated with increased proliferation, high tumor grade, HER2 amplification as well as estrogen receptor (ER) and progesterone receptor (PR) negativity [25,26]
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