Sc. Heffelfinger et al., STAUROSPORINE-INDUCED VERSUS SPONTANEOUS SQUAMOUS METAPLASIA IN PREMENOPAUSAL AND POSTMENOPAUSAL BREAST-TISSUE, Journal of cellular physiology, 176(2), 1998, pp. 245-254
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.