STAUROSPORINE-INDUCED VERSUS SPONTANEOUS SQUAMOUS METAPLASIA IN PREMENOPAUSAL AND POSTMENOPAUSAL BREAST-TISSUE

Breast cancers from pre-vs, postmenopausal women display unique charac teristics that may be related to differences in epithelial differentia tion between these two populations. In addition to lobular development , lactational changes, and involution, breast epithelium can undergo m etaplastic alterations, often in association with carcinoma. Because p rotein kinase C (PKC) regulates differentiation and proliferation in m any cell types, we asked whether modulation of PKC activity could defi ne biochemical differences in breast epithelium from pre-vs, postmenop ausal women. Organ cultures of normal human breast were treated with P KC agonists and antagonists. Epithelial differentiation was evaluated based on morphologic criteria and the expression of cell-type specific proteins. Staurosporine, a nonspecific but extremely potent inhibitor of PKC, induced squamous metaplasia in eight of eight cases within 2 weeks of treatment. Other inhibitors of PKC, such as calphostin C and tamoxifen, had no effect on epithelial differentiation. Long-term trea tment with phorbol esters also did not induce squamous metaplasia. How ever, stimulation of cAMP levels by forskolin and isobutyl-methyl-xant hene (IMX) rapidly induced squamous metaplasia, as has been previously reported. Surprisingly, squamous metaplasia occurred in 10 of 12 cult ures derived from postmenopausal women in the absence of exogenous age nts. Untreated cultures derived from premenopausal women never develop ed th is type of epithelium (0 of 11). Therefore, breast epithelium fr om pre-and postmenopausal women responded differently to in vitro cult ure. Forskolin/lMX or staurosporine can reproduce these conditions, ac ting independent of menopausal status. Because staurosporine's action was unique among PKC inhibitors, staurosporine may induce squamous met aplasia of breast epithelium by a PKC-independent mechanism. (C) 1998 Wiley-Liss, Inc.