Estrogen Signalling Suppresses the Expression of IGFBP-7, a Potential Tumor Suppressor Genes

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-07
Sumanta Chatterjee1, Pratima Basak1, Steve Weger1, Ketan Badiani2, Leigh C Murphy3 and Afshin Raouf*1
1University of Manitoba, Winnipeg, MB, Canada, 2CancerCare Manitoba, Winnipeg, MB, Canada, 3University of Manitoba
Estrogens and insulin-like growth factors (IGFs) play essential roles in the normal breast development as well breast carcinogenesis. Both of these growth factors have been shown to activate multiple signaling pathways leading to proliferation of hormone responsive breast cancer cells. Recent evidence suggests that IGF binding proteins (IGFBPs can modulate expression and activity of Estrogen Receptor alpha (ERα). In addition to limiting the bioavailability of the IGFs, the IGFBPs have been shown to act in IGF-independent manner to function as oncogenes or tumor suppressor genes. IGFBP-7 has been show to act as a potential tumor suppressor in breast, colon and liver cancers. Notably, IGFBP-7’s expression is lost in the high-grade invasive breast cancers and it low expression is associated with reduced patient survival. In vivo, IGFBP-7 expression can suppress the proliferation breast cancer cells in immunodeficient mice. Also, in colon and liver cancers expression of IGFBP-7 is lost due to promoter methylation or loss of hetrozygosity, respectably. These data suggest a role for IGFBP-7 may act as a potential tumor suppressor. In this study, we investigated if estrogen signalling regulates the expression of IGFBP-7 gene in ERα+ breast cancer cells. Interestingly, we found that IGFBP-7 protein and RNA are weakly expressed in the ERa+ MCF7 and T47D cells but are strongly expressed in the ERα negative MDA-MB-231 cells. To determine if estrogen signaling suppresses IGFBP-7 expression, we cultured the MCF-7 and T47D cells in estrogen-reduced growth conditions for 24 hour and observed an 8-fold (P<0.01) increased in IGFBP-7 transcripts and protein levels. Furthermore, addition of an ERα-antagonist, Fulvestrant, further increased the IGFBP-7 gene expression by an additional 8 folds (P<0.0001). When ERα was ectopically expressed in ER negative MDA-MB-231 cells, IGFBP7 transcript level was decreased by 3.2 folds (P<0.01). Similarly to breast cancer cells, our preliminary observations suggest that estrogen signalling suppresses IGFBP-7 expression in the ERα positive normal human breast epithelial cells, suggesting that ERa-IGFBP7 signaling axis may be part of the normal breast development. Taken together, our observations suggest that suppression of a tumor suppressor gene, IGFBP7, due to increased estrogen signalling may lead to initiation of ER positive breast tumors. Understanding the mechanisms by which estrogen signalling regulates the expression of a potential endocrine tumor suppressor factor may lead to the development of effective ways to detect ER positive breast cancers at an early, premalignant stage.

Nothing to Disclose: SC, PB, SW, KB, LCM, AR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by a research grant from the CancerCare Manitoba Research Foundation to AR.