title: Individual-specific variation in the respiratory activities of HMECs and their bioenergetic response to IGF1 and TNFα.
abstract: Metabolic reprograming is a hallmark of cancer cells. However, the roles of pre-existing differences in normal cells metabolism toward cancer risk is not known. In order to assess pre-existing variations in normal cell metabolism, we have quantified the inter-individual variation in oxidative metabolism of normal primary human mammary epithelial cells (HMECs). We then assessed their response to selected cytokines such as insulin growth factor 1 (IGF1) and tumor necrosis factor alpha (TNFα), which are associated with breast cancer risk. Specifically, we compared the oxidative metabolism of HMECs obtained from women with breast cancer and without cancer. Our data show considerable inter-individual variation in respiratory activities of HMECs from different women. A bioenergetic parameter called pyruvate-stimulated respiration (PySR) was identified as a key distinguishing feature of HMECs from women with breast cancer and without cancer. Samples showing PySR over 20% of basal respiration rate were considered PySR+veand the rest as PySR-ve. By this criterion, HMECs from tumor-affected breasts (AB) and non-tumor affected breasts (NAB) of cancer patients were mostly PySR-ve(88% and 89%, respectively), while HMECs from non-cancer patients were mostly PySR+ve(57%). This suggests that PySR-ve/+vephenotypes are individual-specific and are not caused by field effects due to the presence of tumor. The effects of IGF1 and TNFα treatments on HMECs revealed that both suppressed respiration and extracellular acidification. In addition, IGF1 altered PySR-ve/+vephenotypes. These results reveal individual-specific differences in pyruvate metabolism of normal breast epithelial cells and its association with breast cancer risk.
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.|Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts.
authors.forename: Sallie S
authors.initials: SS
authors.lastname: Schneider
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Henchey
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.
authors.forename: Nazneen
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Morin
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.|Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts.
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Jerry
authors.affiliation: Division of Hematology Oncology, Department of Medicine at Baystate Medical Center/Tufts University School of Medicine, Springfield, Massachusetts.
authors.forename: Grace
authors.initials: G
authors.lastname: Makari-Judson
authors.affiliation: Division of Anatomic and Clinical Pathology, Department of Pathology at University of Massachusetts Medical School (UMMS)-Baystate Regional Campus, Springfield, Massachusetts.
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Crisi
authors.affiliation: Division of Surgical Oncology, Department of Surgery at University of Massachusetts Medical School (UMMS)-Baystate Regional Campus, Springfield, Massachusetts.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Arenas
authors.affiliation: Pioneer Valley Plastic Surgery, Springfield, Massachusetts.
authors.forename: Melissa
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Division of Surgical Oncology, Department of Surgery at University of Massachusetts Medical School (UMMS)-Baystate Regional Campus, Springfield, Massachusetts.
authors.forename: Holly S
authors.initials: HS
authors.lastname: Mason
authors.affiliation: Pioneer Valley Life Sciences Institute (PVLSI), Springfield, Massachusetts.|Divisions of Endocrinology, Diabetes and Metabolism, Department of Medicine at Baystate Medical Center /Tufts University School of Medicine, Springfield, Massachusetts.|Department of Biology, University of Massachusetts, Amherst, Massachusetts.
authors.forename: Nagendra
authors.identifier: http://orcid.org/0000-0002-6202-2673
authors.initials: N
authors.lastname: Yadava
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype; D019289:Pyruvic Acid / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D019289:Pyruvic Acid
keywords: IGF1; TNFα; bioenergetics; human mammary epithelial cells (HMECs); oxidative phosphorylation; respiration; respiratory chain