The mevalonate pathway has emerged as a promising target for several solid tumors. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of this pathway, and are commonly used to treat patients with hypercholesterolemia. Pleiotropic antitumor mechanisms of statins have been demonstrated for several human cancer types. However, cancer cells differ in their individual statin sensitivity and some cell lines have shown relative resistance. In this study we demonstrate, that the human breast cancer cell lines MDA-MB-231, MDA-MB-468, MCF-7, and T47D are differentially affected by statins. Whereas the vitality of MDA-MB-231 and MDA-MB-468 cells was reduced by up to 60% using atorvastatin, simvastatin, or rosuvastatin (p < 0.001), only marginal effects were seen in T47D and MCF-7 cells following exposure to statins. Statin treatment led to an upregulation of HMGCR mRNA and protein expression by up to sixfolds in the statin-resistant cells lines (p < 0.001), but no alterations of HMGCR were observed in the statin-sensitive MDA-MB-231 and MDA-MB-468 cells. The knockdown of HMGCR prior to statin treatment sensitized the resistant cell lines, reflected by a 70% reduction in vitality, increased apoptotic DNA fragmentation (sixfold) and by accumulation of the apoptosis marker cleaved poly-ADP ribose polymerase. Statins induced a cleavage of the sterol-regulatory element-binding protein (SREBP)-2, a transcriptional activator of the HMGCR, in T47D and MCF-7 cells. The inhibition of SREBP-2 activation by co-administration of dipyridamole sensitized MCF-7 and T47D cells for statins (loss of vitality by 80%; p < 0.001). Furthermore, assessment of a statin-resistant MDA-MB-231 clone, generated by long-term sublethal statin exposure, revealed a significant induction of HMGCR expression by up to 12-folds (p < 0.001). Knockdown of HMGCR restored statin sensitivity back to levels of the parental cells. In conclusion, these results indicate a resistance of cancer cells against statins, which is in part due to the induction of HMGCR.

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Background Semaphorin 4D (Sema4D) is a glycoprotein that inhibits bone formation and has been associated with cancer progression and the occurrence of bone metastases. Recently, Sema4D expression has been linked to estrogen signaling in breast cancer. Endocrine therapies like tamoxifen and aromatase inhibitors (AI) are a standard therapeutic approach in hormone receptor positive breast cancers. Tamoxifen exerts ER-agonistic effects on bone, whereas AI negatively affect bone health by increasing resorption and fracture risk. The effect of endocrine therapies on circulating Sema4D levels in breast cancer patients has not been investigated yet. Methods We measured circulating Sema4D plasma levels at primary diagnosis and in a follow-up sample 12 months after surgery in a cohort of 46 pre- and postmenopausal women with primary estrogen receptor positive breast cancer receiving adjuvant tamoxifen or AI. Results The mean baseline levels ± SD for Sema4D were 441.6 ± 143.4 pmol/l. No significant differences in total plasma Sema4D were observed when stratifying the patients according to age, menopausal status, tumor subtype, nodal and hormone receptor status, or tumor size. However, Sema4D levels were significantly reduced by 28% ( p <0.001) in tamoxifen treated patients 12 months after surgery, whereas no alteration was observed in patients treated with AI. Conclusion This finding potentially represents an additional mechanism of the bone-protective properties of tamoxifen and further emphasizes a link between Sema4D and estrogen receptor signaling.