Cigarette smoke induces cell motility via platelet-activating factor accumulation in breast cancer cells: a potential mechanism for metastatic disease

Abstract

Most cancer deaths are a result of metastasis rather than the primary tumor. Although cigarette smoking has been determined as a risk factor for several cancers, its role in metastasis has not been studied in detail. We propose that cigarette smoking contributes to metastatic disease via inhibition of breast cancer cell platelet-activating factor acetylhydrolase (PAF-AH), resulting in PAF accumulation and a subsequent increase in cell motility. We studied several breast cell lines, including immortalized mammary epithelial cells (MCF-10A), luminal A hormone positive MCF-7, basal-like triple negative MDA-MB-468, and claudin-low triple-negative highly metastatic MDA-MB-231 breast tumor cells. We exposed cells to cigarette smoke extract (CSE) for up to 48 h. CSE inhibited PAF-AH activity, increased PAF accumulation, and increased cell motility in MDA-MB-231 metastatic triple negative breast cancer cells. The calcium-independent phospholipase A2 (iPLA2) inhibitor, (S) bromoenol lactone ((S)-BEL) was used to prevent the accumulation of PAF and further prevented the increase in cell motility seen previously when cells were exposed to CSE. Thus, iPLA2 or PAF may represent a therapeutic target to manage metastatic disease, particularly in triple-negative breast cancer patients who smoke.

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…Taken together with the fi nding that inhibition of iPLA 2 ␤ , but not iPLA 2 ␥ , prevented increases in PAF in WT cells suggests that iPLA 2 ␤ modulation of PAF production is a factor in cancer cell metastasis. Consistent with these fi ndings, cigarette smoke extract increased PAF accumulations and increased cell motility in MDA-MB-231 breast tumor cells, and these effects were mitigated by iPLA 2 ␤ inhibition ( 378 ). Recently, unicortin, a member of the corticotrophin-releasing factor family, was shown to promote hepatic cancer cell line migration by upregulating cPLA 2 and suppress migration by downregulating iPLA 2 ␤ at the transcriptional level ( 379 ).…”

Recent insights into cigarette smoking as a lifestyle risk factor for breast cancer

“…Epithelial markers, such as E-cadherin and B-catenin, were decreased upon nicotine exposure, whereas mesenchymal markers, such as fibronectin and vimentin, were increased 11. We showed increased cell motility in MDA-MB-231 breast cancer cells exposed to CSE, which could be abrogated by inhibition of calcium-independent phospholipase A 2 (iPLA 2 ), a precursor of platelet-activating factor (PAF) 15. CSE treatment also resulted in increased PAF and PAF receptor (PAF-R) expression 15.…”

O conhecimento de mulheres sobre os métodos para prevenção secundária do câncer de mama

“…The studies therefore show that the carrying out of this examination was less amongst smokers 20 . This fact is worrying as it is an important risk factor for the different types of neoplasia, including those for breasts 6,15,21 . This group of smokers is not able to recognize the disease prevention methods.…”