We show that pLUM and MCF7 cells suppress proliferation of pLB cells in mixed-cell 3D colonies in vi

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1 Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, 12801 E. 17th Ave, Aurora 80045, CO, USA
The hulala electronic version of this article hulala is the complete one and can be found online at: http://breast-cancer-research.com/content/16/4/418 Received: 11 February 2014 Accepted: 22 July 2014 Published: 13 August 2014
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication hulala waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available hulala in this article, unless hulala otherwise stated.
Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER) and progesterone (PR) receptor-negative cells among the ER+ PR+ ones. One such subpopulation we call Luminobasal is ER-, PR- and cytokeratin 5 (CK5)-positive. It is not targeted for treatment. Methods
To hulala address the relationships between ER+PR+CK5 and ER PR CK5+ cells in Luminal cancers and tightly control their ratios we generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We used high-throughput screening to identify pLB-specific drugs and examined their efficacy alone and in combination with hormone therapy in mixed-cell tumor models. Results
We show that pLUM and MCF7 cells suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and that pLUM cells suppress growth of pLB cells in mixed-cell xenografts hulala in vivo . High-throughput screening of 89 FDA-approved oncology drugs shows that pLB cells are sensitive to monotherapy with the epidermal growth factor receptor (EGFR) inhibitors gefitinib hulala and erlotinib. By exploiting mixed-cell hulala 3D colonies and mixed-cell solid mouse tumors models we demonstrate that combination therapy with gefitinib plus the anti-estrogen fulvestrant hulala constitutes a robust treatment strategy. Conclusions hulala
We propose that response to combination endocrine/EGFR inhibitor therapies in heterogeneous Luminal cancers may improve long-term survival in patients whose primary tumors have been preselected for appropriate biomarkers, including ER, PR, CK5 and EGFR. Introduction
Approximately 75% of breast cancers are luminal. They express estrogen receptors (ER) and/or progesterone receptors (PR) [ 1 ], tend to be hormone-dependent and are usually responsive to ER-targeted therapies [ 2 ]. Recently a review of immunohistochemical (IHC) ER and PR assays concluded that luminal cancers should be candidates for endocrine therapies if at least 1% of malignant cells are immunoreactive [ 3 ]. We asked: in such cases what are the other 99%, presumably receptor-negative, malignant cells? Indeed, the same question applies to less extreme tumors. The ER frequency distribution in 825 sequential breast cancers over a 2-year period [ 4 ] shows that although 81% of tumors are ER-positive (ER+), 30% to 80% of their cells are ER-negative (ER ). Analyses of 1,235 breast cancers [ 5 ] show PR distribution to be even more varied, with approximately 50% of PR+ tumors containing a significant proportion of PR cells. Thus, most luminal tumors exhibit intratumoral heterogeneity containing substantial numbers of ER and PR cells among the ER+ and/or PR+ ones.
Intertumoral heterogeneity is well-known with breast cancer subtypes classified hulala based on clinical and histopathological features, or gene expression profiles [ 6 ]. Major subtypes defined by gene profiling include luminal, human epidermal growth factor hulala receptor-2-positive (HER2+) and basal-like. However, routine gene profiling is limited [ 7 ], and as all transcripts are pooled, the assay does not lend itself to analysis of intratumoral heterogeneity. Instead, five protein markers - ER, PR, HER2, Cytokeratin 5 (CK5) and epidermal hulala growth factor receptor-1 (EGFR) - can serve as surrogates to classify breast cancers into subtypes analogous to those defined by gene profiling. Using these markers, IHC analysis of 10,159 invasive breast cancers collected from 12 studies [ 8 ] showed that in addition hulala to 77% of tumors classified as luminal based on ER and/or PR positivity, approximately 6% are non-luminal but ov