Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial.
OBJECTIVE
Cholesterol 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.


METHODS
This 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.


RESULTS
Forty-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).


CONCLUSIONS
We 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.
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. maria.feldt@med.lu.se.
Maria
M
Feldt
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. olof.bjarnadottir@med.lu.se.|Department of Oncology, Skåne University Hospital, Lund, Sweden. olof.bjarnadottir@med.lu.se.
Olöf
O
Bjarnadottir
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. siker.kimbung@med.lu.se.
Siker
S
Kimbung
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. karin.jirstrom@med.lu.se.
Karin
K
Jirström
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. par-ola.bendahl@med.lu.se.
Pär-Ola
PO
Bendahl
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. srinivas.veerla@med.lu.se.
Srinivas
S
Veerla
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. dorthe.grabau@skane.se.
Dorthe
D
Grabau
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. ingrid.hedenfalk@med.lu.se.
Ingrid
I
Hedenfalk
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. signe.borgquist@med.lu.se.|Department of Oncology, Skåne University Hospital, Lund, Sweden. signe.borgquist@med.lu.se.
Signe
S
Borgquist
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
D014408:Biomarkers, Tumor; D002784:Cholesterol; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C530104:CCND1 protein, human; C436291:CDKN1B protein, human; C508053:ERBB2 protein, human