title: Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer.
abstract: Risk biomarkers for estrogen receptor (ER)-negative breast cancer have clear value for breast cancer prevention. We previously reported a set of lipid metabolism (LiMe) genes with high expression in the contralateral unaffected breasts (CUBs) of ER-negative cancer cases. We now further examine LiMe gene expression in both tumor and CUB, and investigate the role of Pre-B-cell leukemia homeobox-1 (PBX1) as a candidate common transcription factor for LiMe gene expression. mRNA was extracted from laser-capture microdissected epithelium from tumor and CUB of 84 subjects (28 ER-positive cases, 28 ER-negative cases, 28 healthy controls). Gene expression was quantitated by qRT-PCR. Logistic regression models were generated to predict ER status of the contralateral cancer. Protein expression of HMGCS2 and PBX1 was measured using immunohistochemistry. The effect of PBX1 on LiMe gene expression was examined by overexpressing PBX1 in MCF10A cells with or without ER, and by suppressing PBX1 in MDA-MB-453 cells. The expression of DHRS2, HMGCS2, UGT2B7, UGT2B11, ALOX15B, HPGD, UGT2B28 and GLYATL1 was significantly higher in ER-negative versus ER-positive CUBs, and predicted ER status of the tumor in test and validation sets. In contrast, LiMe gene expression was significantly lower in ER-negative than ER-positive tumors. PBX1 overexpression in MCF10A cells up-regulated most LiMe genes, but not in MCF10A cells overexpressing ER. Suppressing PBX1 in MDA-MB-453 cells resulted in decrease of LiMe gene expression. Four binding sites of PBX1 and cofactor were identified in three lipid metabolism genes using ChIP-qPCR. These data suggest a novel role for PBX1 in the regulation of lipid metabolism genes in benign breast, which may contribute to ER-negative tumorigenesis.
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Ali
authors.initials: A
authors.lastname: Shidfar
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: David
authors.initials: D
authors.lastname: Ivancic
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Manish
authors.initials: M
authors.lastname: Ranjan
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Liannian
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Choi
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Parimi
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Demirkan B
authors.initials: DB
authors.lastname: Gursel
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Najor
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL.|Department of Pharmacology, Rush University Medical Center, Chicago, IL.
authors.forename: Abde M
authors.initials: AM
authors.lastname: Abukhdeir
authors.affiliation: Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.|Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Denise
authors.initials: D
authors.lastname: Scholtens
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.|Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Seema A
authors.identifier: 0000-0002-6307-2023
authors.initials: SA
authors.lastname: Khan
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008875:Middle Aged; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C083400:PBX1 protein, human
keywords: PBX1; contralateral breast; estrogen receptor; lipid metabolism