Abstract
Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment.
Highlights
Breast cancer is a leading cause of cancer death in women, with almost half a million deaths worldwide per year [1], mainly because of tumor relapse and metastases [2,3]
In order to evaluate the role of cholesterol and its biosynthetic precursor mevalonate in breast cancer progression, and since the goal of our work was to evaluate whether high cholesterol levels were responsible for greater tumor aggressiveness and resistance phenomena, we supplemented already cholesterol-containing media (10% FBS medium) with the indicated amounts of cholesterol and mevalonate, focusing our attention on the ability of the two metabolites to activate the ERRα pathway in four different breast cancer cell lines
In all breast cancer cell lines examined, cholesterol and mevalonate treatment induced a significant increase in ERRα expression levels, as well as in the levels of the related protein PGC-1α—the coactivator needed for the activation of the ERRα pathway—by promoting mitochondrial biogenesis [44] (Figure 1)
Summary
Breast cancer is a leading cause of cancer death in women, with almost half a million deaths worldwide per year [1], mainly because of tumor relapse and metastases [2,3]. Cancer recurrence is associated with a resistance to common therapies and, for this reason, research aims to continuously identify new therapeutic targets, in order to overcome this phenomenon In this context, several research studies have focused on lipid metabolism, storage, and mobilization [4,5]. The mevalonate pathway, leading to the synthesis of sterols such as cholesterol and isoprenoids, has emerged as a promising therapeutic target [6,7] In this pathway, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) plays a key role; it catalyzes the production of mevalonate from 3-hydroxy-3-methylglutaryl-CoA and is considered the rate-limiting enzyme for the pathway [8]. Several reports have shown that cholesterol is closely related to the activation of estrogen-related receptor alpha (ERRα), which, for a long time, was considered to be an orphan nuclear receptor [22,23]
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