Breast cancer incidence is increasing, and despite major progress in the treatment, breast cancer is still the leading cause of death from cancer among women. Thus, there is a constant need for new treatment options. Statins are peroral drugs that have been widely used since the early 1990s, due to their well-documented effect of lowering plasma cholesterol levels and preventing cardiovascular disease. Statins have also been recognized for their pleiotropic effects extending beyond their plasma cholesterol-lowering properties, and preclinical experiments have shown that statins exert anti-tumoral effects in breast cancer cell lines. Further, epidemiological studies have shown reduced breast cancer recurrence and mortality among statin users. These findings have led to the conduction of the phase II, window-of-opportunity, MAmmary cancer and STatins trial (MAST), aiming to further explore the statin effects of breast cancer. Papers I and II are based the MAST trial, which included 50 patients who received a high dose of atorvastatin (80mg/day) for two weeks during the treatment-free window between diagnosis and breast surgery. Before the start of atorvastatin treatment, core needle tumor biopsies were taken from the tumors and blood samples were collected. After two weeks of atorvastatin treatment, tumor tissue was retrieved during the standard surgical procedure and, at the same time, new blood samples were collected.
In paper I, the protein expression of the cell-cycle regulators cyclin D1 and p27 was evaluated by immunohistochemistry on paired samples of formalin-fixed paraffin-embedded tumor tissue, before and after atorvastatin treatment. Project I revealed a significant down‐regulated expression of the oncogene cyclin D1 and a significant up‐regulated expression of the tumor suppressor p27 following two weeks of statin treatment.
In paper II, fresh frozen paired tumor samples pre- and post-atorvastatin treatment were analyzed by extracting lipids from the tumor samples. Cholesterol levels were then measured using a cholesterol quantification assay in order to evaluate changes in the cholesterol levels. The expression of the LDL-receptor (LDLR) was analyzed by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue, pre- and post-atorvastatin treatment. Project II revealed a statin-induced up-regulation of the LDLR and preserved intratumoral cholesterol levels. In vitro experiments on MCF-7 cells treated with atorvastatin were performed for comparison on the cellular level and showed no significant changes in the intracellular cholesterol levels after atorvastatin treatment. There was a higher expression of the LDLR, in agreement with the clinical findings, but it was non-significant.
Paper III is based on the large, prospective population-based Malmo Diet and Cancer Study. Tumor expression of HMGCR, the ratelimiting enzyme of the cholesterol biosynthesis pathway, which is inhibited by statins, was assessed by immunohistochemistry on tissue microarrays from 657 women diagnosed with primary invasive breast cancer between the years of 1991–2010. Tumoral expression of HMGCR was found to be associated with unfavorable tumor characteristics. The associations between statin use, HMGCR expression, and breast cancer mortality were investigated but no statistically significant associations were found.
Paper IV is a descriptive publication of a clinical phase II trial – ABC-SE – in which the effect and tolerability of atorvastatin in combination with endocrine based treatment among patients with advanced breast cancer will be compared to standard endocrine based treatment. The goal of this study is to improve the understanding of the mechanisms behind resistance to endocrine treatment of breast cancer, and also to test the hypothesis that the addition of statins will enhance the effect of the endocrine based treatment. In conclusion, these results demonstrate new insights into the mechanisms of statins in breast cancer, which together with earlier published studies, and hopefully the results from the ABC-SE trial, will form the basis for future conduction of large, phase III randomized clinical trials, which are needed to clarify the role of statins in breast cancer.
- Institutionen för kliniska vetenskaper, Lund
- Borgquist, Signe, handledare
- Belting, Mattias, Biträdande handledare
- Jirström, Karin, Biträdande handledare
- Kimbung, Siker, Biträdande handledare
|Tilldelningsdatum||2021 feb. 5|
|Status||Published - 2021|
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund
Name: Lindström, Linda
Title: Associate Professor
Affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm