Expression of DNA damage response genes indicate progressive breast tumors.
To assess how the abnormal expression of DNA damage response (DDR) genes correlate with oncogenesis, we analyzed mRNA levels of ATM-CHK2-P53 axis in 65 sporadic breast tumors by real-time PCR followed by evaluation of P53 protein and its activation status in representative samples. Univariate analysis showed a significantly higher transcript level for ATM (P=0.002), MDM2 (P=0.015) and p21 (P=0.013) in stage 1 tumors when compared against those of later stages. Although p53 transcript levels showed the characteristic increase in stage 1, a fourfold increase of p53 in N3 tumors than other nodal stages (P=0.0007) significantly increased its expression in stage 3B. The accumulated p53 at stage 3B, confirmed also at the protein level (P=0.012), was rendered nonfunctional by reduced P53 activation (p-P53Ser15; P=0.00007) or increased rate of mutation, substantiated further by the corresponding failure of upregulation of downstream genes, MDM2 and p21. We conclude that the alteration of DDR expression facilitates tumor progression and its possible therapeutic implications need to be studied in future.
Gochhait
Sailesh
S
National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, Aruna Asafali Road, New Delhi-110067, India.
Dar
Surabhi
S
Pal
Ranjana
R
Gupta
Pawan
P
Bamezai
Rameshwar N K
RN
D000483:Alleles; D001943:Breast Neoplasms / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018076:DNA, Complementary; D005819:Genetic Markers; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2