AROMATASE AND ESTROGEN BIOSYNTHESIS
[in Menopause - Hormones and Cancer]
edited by M. Neves -e-Castro and B.G. Wren 2002
[CH2 p9-13]

1. no relationship between breast cancer and plasma levels of estrogen is observed!
   
   1. active uptake from the circulation plays no role in the accumulation of estradiol in tumors
      
   2. estrogens are produced locally, within the tumor thru aromatase activity!
      
      1. postmenopausal, serum-to-tumor gradient exists for estrogen, particularly estradiol
         
      2. breast tumor concentrations of estrogen is same for pre- and postmenopausal women
         
      3. local estrogen contribution often exceeds 50%, especially in postmenopausal women
         
      4. most information we have is from model systems
         
         
2. enzymes for conversion to estrogens are present in breast tumor and exists in the fatty tissue surrounding breast tumor
   
   
   1. estrogens that stimulate tumor growth are converted locally in the fatty tissue surrounding the tumors from androgen precursors [MHC p11]
      
      
      1. includes 17HSD, aromatase, sulfotransferase, sulfatase
         [see fig1 p10]
         
         
         1. 17HSD (17 hydroxysteroid dehydrogenase)
            
            1. Androstenedione (A) --> Testosterone (T)
               
            2. Estrone (E1).................--> Estradiol (E2)
               
               
         2. Aromatase
            
            1. Androstenedione --> Estrone (E1)
               
            2. Testosterone........--> Estradiol (E2)
               
            3. higher aromatase activity in fatty tissue suggests an interaction between tumor and adjacent adiopose tissue
               
            4. location has not been unequivocally determined
               
               1. using polyclonal antibody, aromatase activity is found in stromal spindle cells and not in malignant epithelial cells.
                  
               2. using monoclonal antibody and in situ hybridization to aromatase, mRNA expression was found mainly in malignant epithelial cells
                  
               3. [ISLT] these distinct functions (aromatase activity and cell growth) are normally compartmentalized in different cell types, but abnormal cells exhibit multiple functions in the in same malignant cell
                  
            5. aromatase inhibitors are first line treatment for metastatic breast disease
               1. decreased local and peripheral aromatase activity has been noted
               2. [ISLT] aromatase inhibitor would only inhibit enlargement of tumors, would not be curative
                  
                  
3. Observations about estrogen
   
   1. Breast Ca incidence rises with age
      
   2. tumor hormone receptor positivity increases with age
      
   3. many tumors grow with estrogen, regress with no estrogen
      
   4. estradiol stimulates many cell growth factors
      
      
4. Hypotheses: immune factors stimulate estrogen-dependent breast tumor growth
   
   1. interaction between malignant epithelial, stromal, adipocytes and macrophage cells
      
   2. evidence that tumor uses a different promotor for expression of aromatase than does adjacent adipose stromal tissue that produces estrogen
      
      
      1. tumor promotors are promotors II and I.3
         
         1. PGE2 is the main cytokine that stimulates cAMP and promotors II and I.3
            
      2. normal promotor is promotor I.4, for normal breast growth
         
         1. class I cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa), in the presence of glucocorticoids stimulates promotor I.4
            
            
            

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