Mechanisms of Altered Control of Proliferation by Cyclic Amp/Protein Kinase A During Mammary Tumor Progression
Annual rept. 1 Jun 1998-31 May 1999
KANSAS UNIV MEDICAL CENTER KANSAS CITY
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We hypothesize that alterations in the regulation of growth by growth factors and cAMP during mammary tumor progression are related to MAP kinase signaling pathways known to be affected by cAMP and pertussis toxin PT-sensitive G proteins. Mammary epithelial cells from normal mouse mammary glands were compared to pregnancy-dependent PDT and ovarian-independent OIT mouse mammary tumors in serum-free, collagen gel cell culture. Previous studies suggested that the ERK cascade is only permissive for proliferation, and cAMP and hormones stimulate proliferation via nonERK PT-sensitive pathways. The possible involvement of superphysiological insulinIGF-I receptor in PT sensitivity was examined. PT-sensitivity of proliferation and ERK activation is observed in the absence of insulin. However, in the presence of insulin, cAMP enhanced PT inhibition of ERK activity suggesting a PT-sensitive interaction of insulinIGF-I pathways with cAMP. Examination of other pathways showed that neither the activation or inhibition of the p38 MAP kinase or changes in raf level correlated with stimulatory or inhibitory effects of cAMP on growth. Lysophosphatidic acid LPA, which affects normal and tumor growth similarly to cAMP, was tested and found to activate MAP kinases ERK, JNK, p38 in normal and OIT. LPA stimulation of JNK and ERK activity but inhibition of growth in OIT emphasizes that inhibition of proliferation in these tumors is does not correlate with MAP kinase inhibition and suggests that the previous observation of JNK inhibition by cAMP in OIT is not relevant to its negative effect on growth.
- Medicine and Medical Research