Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia

Background: Transforming growth factors-beta (TGF-beta s) regulate mammary epitheIiaI cell division. Loss of expression of TGF-beta receptor II (TGF-b eta-RII) is related to cell proliferation and tumor progression. Breast epi thelial hyperplastic lesions lacking atypia (EHLA) are associated with a mi ld elevation in breast cancer risk, We investigated the expression of TGF-b eta-RII in EHLA and the risk of subsequent invasive breast cancer. Methods: We conducted a nested case-control study of women with biopsy-confirmed EH LA who did not have a history of breast cancer or atypical hyperplasia of t he breast. Case patients (n = 54) who subsequently developed invasive breas t cancer were matched with control patients (n = 115) who did not. Formalin -fixed, paraffin-embedded sections of breast biopsy specimens of all 169 pa tients with EHLA were studied by immunohistochemical analysis with antibodi es against TGF-beta-RII, All P values are two-sided. Results: Women with br east EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta -RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectiv ely (P for trend = .008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a h eterogeneous pattern of TGF-beta-RII expression in their normal breast lobu lar units and either greater than 75%, 25%-75%, or less than 25% positive c ells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectiv ely (P for trend =.003). These risks are relative to women with a homogeneo us pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA. Conclusion: This study indicates that loss o f TGF-beta-RII expression in epithelial cells of EHLA is associated with in creased risk of invasive breast cancer.