ABSTRACT
BACKGROUND: Altered cellular metabolism is a hallmark of cancer and some are reliant on glutamine for sustained proliferation and survival. We hypothesise that the glutamine-proline regulatory axis has a key role in breast cancer (BC) in the highly proliferative classes. METHODS: Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1), and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large, well-characterised cohorts. RESULTS: Gain of PYCR1 copy number and high PYCR1 mRNA was associated with Luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the oestrogen receptor (ER)+/human epidermal growth factor receptor (HER2)- high proliferation class (Luminal B) compared with ER+/HER2- low proliferation class (Luminal A) (P=0.030 and P=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the glutamine-proline regulatory axis genes revealed significant associations with molecular subtypes of BC and patient outcome independent of standard clinicopathological parameters (P=0.012). High protein expression of the glutamine-proline enzymes were all associated with high MYC protein in Luminal B tumours only (P<0.001). CONCLUSIONS: We provide comprehensive clinical data indicating that the glutamine-proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.
Subject(s)
Breast Neoplasms/genetics , Glutaminase/genetics , Proline/genetics , Proto-Oncogene Proteins c-myc/genetics , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase/metabolism , Breast Neoplasms/metabolism , Female , Gene Dosage , Gene Regulatory Networks , Genes, myc , Glutaminase/metabolism , Glutamine/genetics , Glutamine/metabolism , Humans , Proline/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Pyrroline Carboxylate Reductases/genetics , Pyrroline Carboxylate Reductases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , delta-1-Pyrroline-5-Carboxylate ReductaseABSTRACT
AIMS: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer; its diagnosis in routine practice can be challenging, and may require immunohistochemical (IHC) characterization if no conventional invasive or in-situ carcinoma is present. Previous IHC studies of MBC often had a small sample size and did not investigate the different histological subtypes. This study aimed to assess the immunoprofile of MBC subtypes in a large series. METHODS AND RESULTS: A total of 172 MBC diagnosed in routine and referral practice in Nottingham during 26 years were reviewed by three breast pathologists. In addition, data on the immunoprofile of 730 MBC in 61 published studies were analysed. The antibodies to a broad spectrum of cytokeratins (AE1/AE3 and MNF116) are most frequently positive in MBC (approximately 80%). Basal cytokeratins (34ßE12, CK5/6, CK14 and CK17) are positive in approximately 70%. Luminal cytokeratins (CK8/18, CK7 and CK19) are positive in approximately 30-60%. Myoepithelial markers are also frequently positive, particularly p63. Oestrogen receptor (ER), progestogen receptor (PR) and HER2 are usually all negative. CD34 (a marker often positive in phyllodes tumours) is consistently negative in MBC. CONCLUSION: This study provides data on the frequency of expression of a wide range of markers in MBC based on a large number of tumours. No consistent immunophenotype was identified and no individual marker was positive in all tumours, most probably reflecting the morphological and molecular heterogeneity of this tumour class and the practical need to use a panel of different antibodies when trying to establish the diagnosis of metaplastic breast carcinoma.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Carcinoma/pathology , Breast Neoplasms/metabolism , Carcinoma/metabolism , Female , Humans , ImmunohistochemistryABSTRACT
We evaluated the pH of four hydrogen peroxide systems over a 28-day period of normal daily use to determine if pH changes occurred which could cause ocular discomfort. Using a Corning Model 10 pH meter, we measured the initial pH of the disinfection and neutralization solutions and the final pH of the neutralization solutions over each system's disinfection and neutralization cycle. The final pH of the four systems did not change significantly over the 28-day period; however, the final pH of two of the hydrogen peroxide systems were consistently closer to the physiological pH of tears than the other two systems evaluated. These findings suggest that initial discomfort experienced over a 28-day period of normal daily use of any of the hydrogen peroxide disinfection systems studied may be due to the individual system used, but not due to pH changes within a system. However, individual sensitivities to pH should be considered.
