Metabotropic glutamate receptor 1 expression and its polymorphic variants associate with breast cancer phenotypes.
Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation and differentiation, has been implicated in melanomagenesis, with ectopic expression of GRM1 causing malignant transformation of melanocytes. This study was undertaken to evaluate GRM1 expression and polymorphic variants in GRM1 for associations with breast cancer phenotypes. Three single nucleotide polymorphisms (SNPs) in GRM1 were evaluated for associations with breast cancer clinicopathologic variables. GRM1 expression was evaluated in human normal and cancerous breast tissue and for in vitro response to hormonal manipulation. Genotyping was performed on genomic DNA from over 1,000 breast cancer patients. Rs6923492 and rs362962 genotypes associated with age at diagnosis that was highly dependent upon the breast cancer molecular phenotype. The rs362962 TT genotype also associated with risk of estrogen receptor or progesterone receptor positive breast cancer. In vitro analysis showed increased GRM1 expression in breast cancer cells treated with estrogen or the combination of estrogen and progesterone, but reduced GRM1 expression with tamoxifen treatment. Evaluation of GRM1 expression in human breast tumor specimens demonstrated significant correlations between GRM1 staining with tissue type and molecular features. Furthermore, analysis of gene expression data from primary breast tumors showed that high GRM1 expression correlated with a shorter distant metastasis-free survival as compared to low GRM1 expression in tamoxifen-treated patients. Additionally, induced knockdown of GRM1 in an estrogen receptor positive breast cancer cell line correlated with reduced cell proliferation. Taken together, these findings suggest a functional role for GRM1 in breast cancer.
Division of Medical Oncology, Department of Medicine, The Cancer Institute of New Jersey/University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
Madhura S
MS
Mehta
Sonia C
SC
Dolfi
Roman
R
Bronfenbrener
Erhan
E
Bilal
Chunxia
C
Chen
Dirk
D
Moore
Yong
Y
Lin
Hussein
H
Rahim
Seena
S
Aisner
Romona D
RD
Kersellius
Jessica
J
Teh
Suzie
S
Chen
Deborah L
DL
Toppmeyer
Dan J
DJ
Medina
Shridar
S
Ganesan
Alexei
A
Vazquez
Kim M
KM
Hirshfield
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000145:classification / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D003710:Demography; D018572:Disease-Free Survival; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D046888:Tissue Array Analysis; D055815:Young Adult
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol