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Invasive lobular carcinoma (ILC) represents ^10% of newly diagnosed breast tumors, accounting for -30,000 cases annually in the US. However, ILC has been understudied as a breast cancer subtype. ILC-specific signaling pathways and responses to endocrine therapies are not well characterized. Recent retrospective analyses of luminal-type breast cancers suggest that ILC patients treated with endocrine therapy have poorer disease-free survival and overall survival than invasive ductal carcinoma (IDC) patients with similar biomarkers. We hypothesize that unique transcriptional control of estrogen receptor-alpha (ERa) by estrogens and anti-estrogens in ILC cells drive a differential response of ILC tumors to endocrine therapies. The ILC cell lines MDA MB 134VI and SUM44PE were used as in vitro models of ILC tumors to examine responses to estradiol (E2) and the anti-estrogens tamoxifen (Tarn), 4-hydroxytamoxifen (4OHT), endoxifen (Bx), and fulvestrant (ICI). We examined cell growth and expression of canonical ERa-regulated genes in response to E2. Cells were also treated with anti-estrogens +/- E2 to examine their ability to inhibit E2-induced growth. To establish a genome-wide profile of ERa-mediated gene regulation in ILC cells, ILC cells were subjected to gene expression microarray analysis following 0-24hrs treatment with 1 nM E2. In parallel to these in vitro studies, in vivo models of ILC are being assessed for endocrine responsiveness, including MDA MB 134VI xenografts and the primary human tumor xenograft HCI-013. We observed that both MDA MB 134VI and SUM44PE are growth-induced by E2 treatment. However, both cell lines also present de novo resistance to Tarn, 4OHT, and Bx. While ICI treatment completely blocked E2-induced growth in MDA MB 134VI, Tarn, 4OHT, and Bx acted as partial agonists. Treatment with these compounds alone induced "-25% growth relative to E2, and E2-induced growth could only be inhibited -75%. Similarly, SUM44PE cells are strongly growth-inhibited by ICI treatment, whereas growth is not reduced by Tarn, 4OHT, or Bx treatment. Consistent with these observations, novel patterns of gene expression are induced by E2 treatment in ILC cells. E2-t.reat.ment induced canonical targets (e.g. GREB1, IGFBP4) in both ILC cell lines. However, in MDA MB 134VI cells only -35% of genes regulated by E2 at 24hrs overlap with those regulated in the IDC cell line MCF-7. Further, a subset of the overlapping genes is differentially regulated between cell types, including ESR1 (1.25-fold and 0.67-fold versus control in MDA MB 134VI and MCF-7, respectively), HOXC6, PMP22, and L1CAM. Examination of these observations in in vivo models is currently ongoing. These data are consistent with the hypothesis that E2 and anti-estrogens differentially regulate ERa-mediated gene expression in ILC cells versus IDC cells. The de novo resistance to tamoxifen observed in ILC cells may correlate with the worse outcomes in ILC patients observed in retrospective analyses. We hypothesize that elucidation of the mechanisms responsible for differential ERa regulation may reveal novel therapeutic targets for treating ILC patients and overcoming endocrine resistance. [ABSTRACT FROM AUTHOR]