Abstract
Abstract Background: Metastasis in ER-positive (+) breast cancer (BC) occurring years to decades after initial diagnosis presents a daunting challenge for clinical care and preclinical research due to limited known key players and experimental models. FOXA1 is a pioneer factor for ER-chromatin binding and function, and is highly expressed in ER+ BC metastases, yet the underlying mechanism is unclear. Tumor-secreted proteins play a crucial role in the reciprocal interplay between cancer cells and host microenvironmental factors at both primary and secondary sites. We hypothesized that high FOXA1 provokes an ER-dependent transcriptional program that includes a unique pro-tumorigenic secretome essential for promoting ER+ BC metastasis. Methods: A lentiviral doxycycline (Dox)-inducible FOXA1 overexpression vector and a dual luciferase/GFP (LG) tracking vector were integrated to construct a stable MCF7-LG/FOXA1 cell model. Ovariectomized nude mice bearing MCF7-LG/FOXA1 xenografts in the presence of exogenous estrogen (E2) were randomized to ± Dox, each with continued E2, E2 deprivation (ED), or tamoxifen (Tam). Survival surgery removing the therapy-naïve (E2 arm) and relapsed (ED/Tam arms) tumors was performed when tumors reached ∼1000 mm3. All mice then received ED/Tam 'adjuvant' therapy, with longitudinal luminescence imaging to monitor local/distant recurrences. Mice were or will be euthanized at the ethical end-point. Integrative bioinformatics was performed using RNA-seq and FOXA1/ER ChIP-seq data from our preclinical models to identify secretome targets for functional intervention. Times to tumor regression (TTR) and progression (TTP) were defined by when the tumor reached half or twice the volume at randomization. Results: Median (m) TTR was achieved in ED (31/34 days, -/+Dox, P = 0.184) but not in Tam groups — Tam delayed tumor growth but failed to prevent progression in all mice with mTTP of 94/93 days (-/+Dox, P = 0.517). Despite no difference in mTTP at Tam-/+Dox, a quarter of +Dox tumors (3/12) had volume doubled by day 11. No metastases were observed by imaging in any of the mice before surgery ('neoadjuvant' setting). Local relapse and lymph-node/lung metastases were detected after surgery ('adjuvant' setting). At day 90 in the adjuvant Tam group with previously relapsed tumors, +Dox mice succumbed to metastasis more often than -Dox mice (7/8 vs. 3/10, P = 0.023). Compared to the adjuvant Tam+Dox mice with previous therapy-naïve tumors, the Tam+Dox with previously relapsed tumors showed higher distant metastasis rate (7/8 vs. 5/14, P = 0.026). Analysis of the ED setting is pending due to late recurrence. Data integration and functional study revealed a set of cytokines, growth factors, and extracellular matrix components (including IL-8, CTGF, and LOX), regulated by FOXA1 often in conjunction with ER, that are highly involved in FOXA1-induced metastasis. Global secretome profiling by mass spectrometry and target validation are ongoing. Conclusions: FOXA1 overexpression increases metastatic potential in ER+ BC. We established a pertinent metastatic xenograft mouse model to characterize a pro-metastatic secretome with diagnostic and therapeutic potential for treating metastatic ER+ BC. Citation Format: Fu X, Pereira R, Zhao D, Jung SY, Jeselsohn R, Creighton CJ, Shea M, Nardone A, Angelis CD, Tsimelzon A, Wang T, Gutierrez C, Huang S, Edwards DP, Rimawi MF, Hilsenbeck SG, Brown M, Chen K, Osborne CK, Schiff R. FOXA1 induces a pro-metastatic secretome through ER-dependent and independent transcriptional reprogramming in endocrine-resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD2-04.
Published Version
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