title: Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity.
abstract: BACKGROUND
  Co-Activator Arginine Methyltransferase 1(CARM1) is an Estrogen Receptor (ER) cofactor that remodels chromatin for gene regulation via methylation of Histone3. We investigated CARM1 levels and localization across breast cancer tumors in a cohort of patients of either European or African ancestry.
  
  
  METHODS
  We analyzed CARM1 levels using tissue microarrays with over 800 histological samples from 549 female cancer patients from the US and Nigeria, Africa. We assessed associations between CARM1 expression localized to the nucleus and cytoplasm for 11 distinct variables, including; ER status, Progesterone Receptor status, molecular subtypes, ethnicity, HER2+ status, other clinical variables and survival.
  
  
  RESULTS
  We found that levels of cytoplasmic CARM1 are distinct among tumor sub-types and increased levels are associated with ER-negative (ER-) status. Higher nuclear CARM1 levels are associated with HER2 receptor status. EGFR expression also correlates with localization of CARM1 into the cytoplasm. This suggests there are distinct functions of CARM1 among molecular tumor types. Our data reveals a basal-like subtype association with CARM1, possibly due to expression of Epidermal Growth Factor Receptor (EGFR). Lastly, increased cytoplasmic CARM1, relative to nuclear levels, appear to be associated with self-identified African ethnicity and this result is being further investigated using quantified genetic ancestry measures.
  
  
  CONCLUSIONS
  Although it is known to be an ER cofactor in breast cancer, CARM1 expression levels are independent of ER. CARM1 has distinct functions among molecular subtypes, as is indicative of its sub-cellular localization and it may function in subtype etiology. These sub-cellular localization patterns, indicate a novel role beyond its ER cofactor function in breast cancer. Differential localization among ethnic groups may be due to ancestry-specific polymorphisms which alter the gene product.
authors.affiliation: The Institute for Genomics and Systems Biology, University of Chicago Biological Sciences Division, Chicago, IL 60637, USA. mbdavis@uga.edu
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Davis
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.forename: Shiyao
authors.initials: S
authors.lastname: Wang
authors.forename: Jaxk
authors.initials: J
authors.lastname: Reeves
authors.forename: Andrey
authors.initials: A
authors.lastname: Khramtsov
authors.forename: Dezheng
authors.initials: D
authors.lastname: Huo
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
mesh_terms: D000328:Adult; D044383:Black People; D001943:Breast Neoplasms / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D057890:Epigenomics; D005260:Female; D006801:Humans; D008875:Middle Aged; D009549:Nigeria; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014481:United States; D044465:White People; D001741:Black or African American
chemical_list: D011484:Protein-Arginine N-Methyltransferases; D018719:Erb-b2 Receptor Tyrosine Kinases; C119966:coactivator-associated arginine methyltransferase 1; C508053:ERBB2 protein, human