Circulating Levels of PCSK9, ANGPTL3 and Lp(a) in Stage III Breast Cancers

Abstract

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Growing evidence demonstrate the role of cholesterol in sustaining tumor growth and metastasis in a large variety of cancers. Given that cholesterol-lowering drugs are being used in combination to lower cholesterol levels in cardiovascular diseases, it becomes intuitive to verify whether these drugs could be used to induce a sufficient depletion of cholesterol to impede tumor progression. A new generation of lipid-lowering drugs are available, yet the circulating levels of their targets have not been determined in cancers. Given that drugs directed against PCSK9 (drugs: evolocumab, alirocumab), ANGPTL3 (drug: evinacumab) and Lp(a) (drug: AKCEA-APO(a)-LRx) are available, it would be important to assess their circulating levels in cancers. Elevated levels of these proteins would pave the way to trials studying lipid-lowering drugs as adjuvant treatments in cancers. <h3>Objective/Purpose</h3> To compare circulating levels of PCSK9, ANGPTL3, and Lp(a) in women with stage III breast cancer versus women with a premalignant or benign breast lesion. <h3>Methods</h3> Twenty-three plasma samples from women diagnosed with a stage III breast cancer (ductal, lobular or mixed) were matched for age with twenty-three plasma samples from women bearing a premalignant (stage 0, N=9) or benign (N= 14) breast lesion. The lipid profile (total cholesterol, HDL cholesterol and triglycerides) was measured on a Siemens Vista platform. LDL were calculated with the Friedewald formula. Apo B and Lp(a) were measured on a Roche Modular platform. ANGPTL3 and PCSK9 plasma levels were quantitated by ELISA (kits purchased from Abcam and Biolegend, respectively). Statistical analysis was performed using SAS (version 9.4) software. <h3>Results</h3> PCSK9 levels were significantly higher in women with stage III breast cancer compared to age-matched counterparts presenting a benign lesion (95.92 +/- 15.67 ng/ml vs. 78.54 +/- 11.12 ng/ml, p< 0.05, n=14). Moreover, PCSK9 concentrations (ng/ml) positively correlated with the disease severity (benign, stage 0, stage III) (r=0.34, p<0.05, n=46). In contrast, ANGPTL3 and Lp(a) plasma levels did not display any association with breast disease status. <h3>Conclusions</h3> The data suggest that PCSK9 levels increase with the severity of breast carcinoma. We hypothesize a mechanism whereby tumoral uptake of cholesterol triggers hepatic secretion of PCSK9 to maintain cholesterolemia. PCSK9 inhibition in combination with statin therapy may be an interesting pharmacological approach to deprive tumors of cholesterol, enhance anti-tumor immune response and impede cancer progression.