Anti-hormone therapies such as Tamoxifen, are widely used to treat breast cancer patients. A small but significant number of patients receiving tamoxifen will not respond or will develop resistance. Although many mechanisms have been suggested which may play a role in tamoxifen resistance, the mechanisms have not yet been fully elucidated. Tamoxifen resistant breast cancer (TamR) cell lines have been shown to have increased expression of a number of cell signalling mediators including EGF receptor[1], ERK-1/2 [2], Src [3] and PKC α and δ isoforms[4]. These cells are stimulated to proliferate by a number of growth factors including members of the Insulin like growth factor (IGF) family. We have previously shown that IGF-1 increases PKC-δ activity in the parent MCF-7 cell lines [5]. Now using adenoviral delivery of dominant negative forms of PKC- α and δ we have investigated the role of these PKC isoforms in tamoxifen resistant breast cancer cell proliferation. IGF-I and II stimulate TamR cell proliferation 162% and 274% respectively v. control (n= 6). Expression of the PKC-δ dominant negative mutant inhibited control cell proliferation by 15% and significantly reduced growth stimulation by IGF-I (by 48%) and by IGF-II (by 70%). Similarly, the PKC-α dominant negative mutant inhibited control cell proliferation by 42%. Expression of dominant negative PKC-α inhibited IGF-I stimulated growth by 37% and IGF-II stimulated growth by 63%. Thus increased expression of PKC- α and δ in tamoxifen resistant cell lines appear to contribute to the cells’ proliferative response to both IGF-I and II, with PKC-δ appearing to have a particularly important role in IGF-II signalling.