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Lipid metabolism reprogramming and Trastuzumab resistance in Breast cancer cell lines overexpressing the ERBB2 membrane receptor.

ABSTRACT: ERBB2 overexpression is associated with aggressive breast cancer (BCa) disease. The introduction in the clinic of Trastuzumab (Tz) targeting this receptor has considerably improved patient outcomes. However, de novo or acquired resistance to Tz occurs and negatively impacts prognosis. Many molecular mechanisms have been reported in the development of Tz resistance. This study aimed to establish whether common mechanisms could be identified in in vitro models of acquired BCa Tz resistance. In particular, we used widely available ERBB2+ Breast cancer cell lines BT474, MDA-MB-361, and SKBR-3, adapted in vitro to grow in Tz concentration ten times higher than the saturation one. Wt and TZ-R cells were studied to address changes in phenotype, proliferation, apoptosis, and ERBB2 membrane expression that did not highlight alterations common to the three cell lines. We used high-resolution mass spectrometry analysis to gain insight into the mechanisms associated to the adaptation of continuous growth in very high Tz concentration. This analysis identified a common set of differentially expressed proteins (DEPs) in Tz-R vs. wt cells. Bioinformatic tools available in the public domain revealed that all three Tz-R cell models shared modulation of proteins involved in the metabolism of lipids, organophosphate biosynthetic process, and macromolecule methylation. This data was partially supported by evidence of a higher number of lipid droplets in TZ-R SKBR-3 with respect to wt. In conclusion, our data strongly support previous evidence that complex metabolic adaptation, including lipid metabolism, protein phosphorylation, and possibly chromatin remodeling, may fuel Tz resistance. At the same time, identifying a common set of 10 DEPs in all three TZ-resistant cell lines may provide possible novel targets for therapeutic intervention.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Epithelium, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Gabriela Coronel Vargas

LAB HEAD: Patrizio Castagnola

PROVIDER: PXD037657 | Pride | 2023-05-23

REPOSITORIES: Pride

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Project description:Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Estrogen receptor alpha (ERa) is overexpressed in 70% of diagnosed BCa patients and androgen receptor (AR) is overexpressed in 80-90% of diagnosed PCa patients. Thus, BCa and PCa patients are given therapy that reduces hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. 15-30% of BCa patients and ≥ 30% of PCa patients that acquire treatment resistance develop tumors enriched in cancer cells with low or no HR accumulation. Furthermore, 15-20% of BCa patients and 10-20% of PCa patients are intrinsically HR-negative (HR-), and thus, have intrinsic resistance to therapy. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERa and AR mRNA in HR-positive (HR+) BCa and PCa cell lines. Additionally, we had identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells, to promote HR-independent survival and tumorigenicity. Methods: To identify changes in global gene expression we performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in BCa and PCa cell lines. We also compared our gene expression data with publicly available data sets from hormone receptor-independent sublines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encode by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in hormone receptor-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HR- cell line viability in response verteporfin, an FDA approved therapy for macular degeneration known to target p62, and we found that verteporfin is cytotoxic for HR- cells lines. Conclusions: Taken together, our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic hormone receptor-independent BCa and PCa.

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Lipid metabolism reprogramming and Trastuzumab resistance in Breast cancer cell lines overexpressing the ERBB2 membrane receptor.

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