Abstract
BackgroundPrevention of triple-negative breast cancer (TNBC) is hampered by lack of knowledge about the drivers of tumorigenesis.MethodsTo identify molecular markers and their downstream networks that can potentially be targeted for TNBC prevention, we analyzed small RNA and RNA sequencing of a cell line model that represent early stages of TNBC development. We have identified direct gene targets of isomiRNA-140-3p and by using cell-based and in vivo model systems we have demonstrated the utility of targeting downstream pathways for prevention of TNBC.ResultsThese analyses showed that 5’isomiRNA of miR-140-3p (miR-140-3p-1) and its novel direct gene targets, HMG-CoA reductase (HMGCR) and HMG-CoA synthase 1(HMGCS1), key enzymes in the cholesterol biosynthesis pathway, were deregulated in the normal-to-preneoplastic transition. Upregulation in the cholesterol pathway creates metabolic vulnerability that can be targeted. Consistent with this hypothesis, we found direct targeting of miR-140-3p-1 and its downstream pathway by fluvastatin to inhibit growth of these preneoplastic MCF10.AT1 cells. However, although, fluvastatin inhibited the growth of MCF10.AT1-derived xenografts, histological progression remained unchanged. The cholesterol pathway is highly regulated, and HMGCR enzymatic activity inhibition is known to trigger a feedback response leading to restoration of the pathway. Indeed, we found fluvastatin-induced HMGCR transcript levels to be directly correlated with the degree of histological progression of lesions, indicating that the extent of cholesterol pathway suppression directly correlates with abrogation of the tumorigenic process. To block the HMGCR feedback response to statins, we treated resistant preneoplastic cells with an activator of AMP-activated protein kinase (AMPK), a brake in the cholesterol feedback pathway. AMPK activation by aspirin and metformin effectively abrogated the statin-induced aberrant upregulation of HMGCR and sensitized these resistant cells to fluvastatin.ConclusionsThese results suggest the potential use of combined treatment with statin and aspirin for prevention of TNBC.
Highlights
Triple negative breast cancer (TNBC) accounts for ~ 5% of the 250,000 annual cases of breast cancer, its more aggressive nature, coupled with its lack of targeted therapy, results in a disproportionate rate of mortality in women with this disease, underscoring the critical need for prevention-based approaches relevant for triple-negative breast cancer (TNBC)
By performing next-generation small RNA and RNA sequencing of this model system, we have recently shown that the majority of micro RNA (miRNA) alterations (> 50%) and gene alterations (> 80%) occur during preneoplastic normal to atypia MCF10A(P) to MCF10.AT1 transition [4]
We report on the functional significance of this variant in TNBC tumorigenesis, mediated by regulation of the cholesterol biosynthesis/mevalonic acid (MVA) pathway, which creates a metabolic vulnerability that can be targeted for breast cancer prevention
Summary
Triple negative breast cancer (TNBC) accounts for ~ 5% of the 250,000 annual cases of breast cancer, its more aggressive nature, coupled with its lack of targeted therapy, results in a disproportionate rate of mortality in women with this disease, underscoring the critical need for prevention-based approaches relevant for TNBC. By performing next-generation small RNA and RNA sequencing of this model system, we have recently shown that the majority of miRNA alterations (> 50%) and gene alterations (> 80%) occur during preneoplastic normal to atypia MCF10A(P) to MCF10.AT1 transition [4]. These results suggest that molecular determination of cell fate occurs early in the development of breast cancer, which creates enormous opportunities for identifying molecular markers and their downstream pathways for prevention of breast cancer. Prevention of triple-negative breast cancer (TNBC) is hampered by lack of knowledge about the drivers of tumorigenesis
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