Abstract
Breast Cancer is the leading cause of cancer deaths in females in Australia. The hormone estrogen is a major aetiological factor in breast carcinogenesis, however, estrogen’s role as a survival factor in breast cancer growth and response to therapy is less well defined. The estrogen-regulated survival gene, BAG-1, is often overexpressed in breast cancer, however, its role in breast carcinogenesis and response to endocrine treatments is poorly defined. This study has shown that BAG-1 overexpression may play a role in
breast cancer initiation by attenuating luminal apoptosis in MCF-10A acini leading to an ablation of lumen formation and that this process was dependent on RAF-1 activation and subsequent enhancement of downstream MAP kinase signalling resulting in ERK-mediated BIM degradation. To determine whether BAG-1 may cooperate with known oncogenes commonly overexpressed in breast cancer such as c-MYC
and therefore play a role in breast cancer progression, BAG-1 was co-overexpressed with c-MYC in the MCF-10A 3-D model. However, c-MYC had no significant effects on apoptosis compared to controls and thus when co-expressed with BAG-1, the functions of BAG-1 predominated resulting mature acini resembled BAG-1 only expressing structures. Furthermore, co-expression did not further enhance the c-MYC-mediated transformed acinar morphology suggesting that BAG-1 does not cooperate with c-MYC to enhance c-MYC mediated tumorigenesis. To understand the role of BAG-1 on the response to antiestrogens in ER+ breast cancer, BAG-1 was overexpressed in the MCF-7 ER+ breast cancer cell line and the response to antiestrogens was investigated. BAG-1 both attenuated tamoxifen-induced apoptosis while enhancing the sensitivity of MCF-7 cells to the growth inhibitory effects of antiestrogens. Furthermore, the latter provides a potential in vitro mechanism for recent clinical data examining the influence of BAG-1 on response to endocrine treatments and outcome in ER+ breast cancer patients. Thus BAG-1 overexpression in a 3-D model, which correlates with mammary acinar morphogenesis in vivo, suggests that
BAG-1 may contribute to breast cancer initiation, however, BAG-1 overexpression also correlated with improved response to endocrine therapy and patient prognosis. An explanation for this apparent dichotomy in BAG-1 function may involve BAG-1 playing an important role during tumour initiation; however, this ultimately leads to the formation of less aggressive, more therapeutically responsive tumours and improved breast cancer patient survival.