Abstract P5-05-06: Cobalamin metabolism in breast cancer
Authors: Collins DA 
Published: May 2016

Cobalamin (Cbl) has two canonical co-enzymatic functions within mammalian cells. In the cytoplasm methylcobalamin promotes the synthesis of methionine, thymidine, and S-adenosylmethionine to sustain the anabolism of proteins, DNA, and multiple methylation reactions, respectively. Within the mitochondria, 5-deoxyadenosylcobalamin (AC) facilitates the final step in the catabolism of branched chain amino acids, odd chain fatty acids and cholesterol for ATP production.

Methods and Findings:

To assess Cbl metabolism within breast tumors, Cbl plasma levels where obtained in 20 women with suspicious breast lesions. Next 0.25 ug of an Indium-111 (In-111) radiolabeled AC analog was intravenously administered and quantitatively imaged at 2-5 hours after injection with single photon emission computed tomography. Within the cohort, 17 were found to have tumors at biopsy, while 3 had benign pathology. Of the 17 breast cancers, 94.1% (16/17) had increased In-111 AC metabolism. Most of the In-111 AC avid breast cancers were in foci of invasive, high nuclear grade ductal carcinoma and were imaged independent of their estrogen (ER), progesterone (PR), or Herceptin (HER2) receptor status. Foci of high grade ductal carcinoma in situ (DCIS), and single cases of invasive lobular, inflammatory and triple negative (TN) tumors were also depicted. Excluding one patient with a large, 7.5cm breast tumor, the average tumor size was 1.9 cm (range 0.7 - 3.4 cm).

The average T:B ratio of the 16 true positive (TP) In-111 AC avid breast cancers was 5.8 (range 2.0-22.5). Four TP patients had ingested Cbl or dexamethasone (DEX) 24 hrs prior to their scans. The average T:B ratios in their tumors was 12.8 (range 5.9- 22.5) with an average Cbl plasma concentration of 1,150 (range 710-2000 ng/L). In the 12 TP patients that had not ingested Cbl or DEX 24 hrs prior to tracer injection, the T:B ratio was 3.5 (2.0-5.6) with an average Cbl plasma concentration of 400 (range 70-580 ng/L). The 3 true negative (TN) scans had an average T:B ratio of 1.2 (range 1.0-1.5). The one false negative (FN) scan was a low grade well differentiated tubular carcinoma with a T:B ratio of 1.8. In these four patients the average Cbl plasma concentration was 402 (range 350-488 ng/L).

Pulse-chase (PC) studies in 8-12 weeks old, 20-25g nude mice burdened with the MDA-MB-231 TN breast tumors demonstrated that the administration of 2.0 ug of non-labeled AC at 2, 8, or 24 hrs prior to the injection of 0.5 ug of In-111 AC increased the In-111 AC uptake within the TN tumors by an average of 21.5%, 67.6%, and 90.6%, respectively. This occurred despite the doses of AC and In-111 AC being 20 and 5 times the respective maximum murine recommended daily allowance for Cbl. The DEX 24 hr PC interval increased In-111 AC uptake within the MDA-MB-231 tumors by 44.8%.

Conclusion:

The Cbl metabolic pathway is upregulated within aggressive breast malignancies and can be biochemically targeted by a simple pulse-chase technique in vivo. The definitive mechanisms underpinning the up-regulated mitochondrial metabolism of Cbl within human breast tumors and the PC methodology remain to be elucidated. Further investigation of Cbl metabolism within benign and malignant breast tissue could potentially yield new molecular targets to detect and treat aggressive breast tumors.

Citation Format: Collins DA. Cobalamin metabolism in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-05-06.