The proposed research aims at at a better definition of the steroidal hormone milieu at the tissue level in the human breast at risk for cancer and to assess some of the pathological and biochemical implications. The major focus will be on fibrocystic disease manifesting macrocysts, a condition imposing risk for breast cancer particularly when associated with family history of cancer. The steroid studies would involve quantification of specific androgens and estrogens - hydroxylated at the 16 alpha- position-in aspirated breast cyst fluid (BCF). These compounds were selected because of their high BCF to blood ratios - implying synthesis proximal to the cyst compartment - and because of the estrogenic potency of 16 alpha-hydroxyestrogens. The steroids to be assayed are the sulfates of 16 alpha hydroxydehydroepiandrosterone, androst-5-ene-3 beta, 16 alpha, 17 beta-triol, 16 alpha--hydroxyestrone and the classical estrogens: estrone, estradiol, and estriol. The concentrations of the hormones will be correlated with those of the univalent ions Na and K. High-K cysts have been associated with apocrine proliferation, a cancer-risk factor. The two important enzyme activities, 16 alpha-hydroxylase and aromatase will be assessed in breast cystic tissue and ostensibly normal duct lobules grown in organ culture. The tissues will be dissected promptly from breast obtained at mastectomy. This model, though subject to interpretation, eliminates the troublesome features of differential clearance and turnover rates in body pools such as the cyst compartment. In parallel, estrogen-sensitive secretory enzymes associated with cell proliferation or transformation will be quantified and characterized. These will include hydrolases that cleave steroid esters, facilitating the release of the parent hormone and plasminogen activator, a known breast tumor marker. A final aspect of the proposal would exploit the MCF-7 breast cancer cell line as a model to test the role of estrogen- sensitive esterases in the control of cell proliferation. This intensive investigation will provide insights into an important facet of the hormonal milieu at the tissue level which can be correlated with indicators of epithelial pathology and hormonal stimulation. All patients in the study are entered in a computer memory bank so that the subsequent course of fibrocystic disease may be assessed in terms of the laboratory findings.
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