title: Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice.
abstract: The emerging links between breast cancer and metabolic dysfunctions brought forth by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status that affects the disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1 transgenic offspring exposed to a metabolically compromised environment imposed by maternal high-fat diet. Control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, compared with control diet exposure. However, doxorubicin-treated tumors from high-fat-diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1) and basal stem cell-like (CD29(hi)CD24(+)) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations (CD29(hi)CD24(+), CD29(lo)CD24(+), CD29(hi)CD24(+)Thy1(+)) in tumors from high-fat-diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat-diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced the ability to form mammosphere and decreased apoptosis, relative to doxorubicin-only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny, and may inform clinical management of disease.
authors.affiliation: Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Maria Theresa E
authors.initials: MT
authors.lastname: Montales
authors.affiliation: Department of PediatricsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Arkansas Children's Hospital Research InstituteUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Stepan B
authors.initials: SB
authors.lastname: Melnyk
authors.affiliation: Department of Pharmaceutical SciencesUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Shi J
authors.initials: SJ
authors.lastname: Liu
authors.affiliation: Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA The Winthrop P Rockefeller Cancer InstituteUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Simmen
authors.affiliation: The Winthrop P Rockefeller Cancer InstituteUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA Department of Internal MedicineUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Y Lucy
authors.initials: YL
authors.lastname: Liu
authors.affiliation: Department of Physiology and BiophysicsUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA The Winthrop P Rockefeller Cancer InstituteUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, USA simmenrosalia@uams.edu.
authors.forename: Rosalia C M
authors.initials: RC
authors.lastname: Simmen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D059305:Diet, High-Fat; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D047368:Tumor Burden / Q000187:drug effects; D051155:Wnt1 Protein / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D004317:Doxorubicin
keywords: breast cancer; doxorubicin; high-fat diet; kynurenine metabolite; stem cells