Antiestrogen therapy has been used successfully to prolong disease-free and overall survival of ER positive
breast cancer patients. However, 50% of patients with ER+ tumors fail to respond to such
therapy or eventually acquire resistance to endocrine
therapy, resulting in
tumor progression and mortality. It is imperative, therefore, to understand the mechanisms that lead to
hormone refractory
breast cancer in order to develop
therapeutics that can modulate the resistance to
antiestrogen therapy. The
protease, ADAM12, can be detected in the urine of
breast cancer patients and its levels correlate with disease status, stage, and
cancer risk. Within the context of this study, the authors have investigated the role of the two distinct
isoforms of ADAM12 in
breast tumor cell proliferation and as potential mediators of endocrine resistance. Using stable clones of ADAM12-overexpressing MCF-7 cells, the authors analyzed proliferation rates of these ER+ breast
tumor cells both in
estrogen-depleted medium and in the presence of the
antiestrogens,
tamoxifen, and
ICI 182,780. Acquired
estrogen resistance in these cells was analyzed using phospho-RTK analysis. Upregulation and phosphorylation of
proteins were detected via immunoprecipitation and immunoblotting. EGFR and MAPK inhibitors were used to explore the mechanism of acquired
estrogen resistance in
breast tumor cells. It was observed that overexpression of the two
isoforms, transmembrane ADAM12-L, and secreted ADAM12-S, in
breast tumor cells promoted
estrogen-independent proliferation. In ADAM12-L-expressing cells,
estrogen-independence was a direct result of increased EGFR expression and MAPK activation, whereas, the mechanism in ADAM12-S-expressing cells may be enhanced IGF-1R signaling. The importance of the EGFR signaling pathway in the
estrogen-independent growth of ADAM12-L expressing cells was highlighted by the effect of EGFR inhibitors
AG1478 and PD15035 or MAPK inhibitor
U0126, each of which abolished the
antiestrogen resistance in these cells. Taken together, these results demonstrate that ADAM12
isoforms confer a proliferative advantage to MCF-7 cells in the absence of
estrogen stimulation, and suggest that downregulation of ADAM12 in combination with endocrine
therapy may represent a useful pharmacological approach to
breast cancer therapy.