The role of aromatase and 17-beta-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer.
BACKGROUND
There is substantial evidence that breast cancer tissue contains all the enzymes responsible for the local biosynthesis of estrogens from circulating precursors. The cytochrome P-450 aromatase enzyme complex is responsible for the conversion of C19 androgens to estrogens and 17-beta-hydroxysteroid dehydrogenase (17-I(2)-HSD) type 1 catalyses the inter-conversion of estrone to the biologically more potent estradiol. The gene encoding for the cytochrome P-450 aromatase is known as CYP19 (15q21.2). It is well established that increased exposure to local estrogens is an important risk factor in the genesis and growth of breast cancer. The aim of this study is to investigate the relationship between CYP19 and 17-beta-HSD type 1A mRNA expression and clinico-pathological parameters of human breast cancer.


METHODS
One hundred and twenty seven tumor tissues and 33 normal tissues were analyzed. The levels of transcription of CYP19 and 17-beta-HSD type 1 were determined using real-time quantitative PCR. The mRNA expression was normalized against CK19. Levels of expression were analyzed against tumorâ's stage, grade, nodal status, local relapse, distant metastasis and survival over a 120A months follow up period. In addition, the levels were analyzed against estrogen receptor (ER) and HER1-4 status.


RESULTS
Overall, high tumor levels of mRNA expression of CYP19 and 17-beta-HSD type 1 correlated with poor survival (p=0.0105 and p=0.0182, respectively). Increased levels of CYP19 mRNA expression positively correlated with disease progression as levels were significantly higher in samples of patients who had distant metastasis and local recurrence and/or died of breast related causes when compared to those who were disease free for >10 years (p=0.0015). We also observed higher levels of CYP19 mRNA in tumor samples compared to normal breast tissue. However, this reached statistical significance only when comparing grade 1 tumors with normal tissue (p=0.01). There was no correlation between CYP19á mRNA expression and tumor stage, lymph node status and tumor grade. There was however a trend for a positive correlation between CYP19 and ER mRNA expressions (p=0.06). No significant difference in 17-beta-HSD type 1 expression between normal and cancerous tissues was observed. In tumor samples, we observed an increase in levels correlating with tumor's grade. This correlation was statistically significant when we compared grade 1 with grade 2 and grade 1 with grade 3 (p=0.0031 and 0.0251, respectively).


CONCLUSIONS
Our study shows that higher levels of the enzymes responsible for the local biosynthesis of estrogens especially aromatase are associated with a poor clinical outcome in patients with breast cancer.
St George's Hospital, Blackshaw Road, London, Tooting, UK.
M
M
Salhab
M J
MJ
Reed
W
W
Al Sarakbi
W G
WG
Jiang
K
K
Mokbel
D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D001141:Aromatase