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Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients.

ABSTRACT: Triple negative breast cancer (TNBC) comprises 15-20% of all invasive breast cancer and is associated with a poor prognosis. As therapy options are limited for this subtype, there is a significant need to identify new targeted approaches for TNBC patient management. The expression of the folate receptor alpha (FR?) is significantly increased in patients with TNBC and is therefore a potential biomarker and therapeutic target. We optimized and validated a FR? immunohistochemistry method, specific to TNBC, to measure FR? expression in a centrally confirmed cohort of 384 patients with TNBC in order to determine if expression of the protein is associated with invasive disease-free survival (IDFS) and overall survival (OS). The FR? IHC demonstrated exceptional performance characteristics with low intra- and interassay variability as well as minimal lot-to-lot variation. FR? expression, which varied widely from sample to sample, was detected in 274 (71%) of the TNBC lesions. In a multivariable model adjusted for baseline characteristics, FR? expression was associated with improved IDFS (HR?=?0.63, p?=?0.01) but not with OS. The results demonstrate the potential of targeting the FR? in the majority of TNBC patients and suggest that variable expression may point to a need to stratify on FR? expression in clinical studies.

SUBMITTER: Norton N

PROVIDER: S-EPMC7000381 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients.

Norton Nadine N Youssef Bahaaeldin B Hillman David W DW Nassar Aziza A Geiger Xochiquetzal J XJ Necela Brian M BM Liu Heshan H Ruddy Kathryn J KJ Polley Mei-Yin C MC Ingle James N JN Couch Fergus J FJ Perez Edith A EA Liu Minetta C MC Carter Jodi M JM Leon-Ferre Roberto A RA Boughey Judy C JC Somers Elizabeth B EB Kalari Krishna R KR Visscher Daniel W DW Goetz Matthew P MP Knutson Keith L KL

NPJ breast cancer 20200204

Triple negative breast cancer (TNBC) comprises 15-20% of all invasive breast cancer and is associated with a poor prognosis. As therapy options are limited for this subtype, there is a significant need to identify new targeted approaches for TNBC patient management. The expression of the folate receptor alpha (FRα) is significantly increased in patients with TNBC and is therefore a potential biomarker and therapeutic target. We optimized and validated a FRα immunohistochemistry method, specific ...[more]

PMID: 32047850

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Project description:Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.

Dataset Information

Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients.

Publications

Folate receptor alpha expression associates with improved disease-free survival in triple negative breast cancer patients.

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