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Human breast cancer invasion signature

ABSTRACT: Introduction: Metastasis of breast cancer is the main cause of death in patients. Previous genome-wide studies have identified gene expression patterns correlated with cancer patient outcome, however these were mostly derived from whole tissue without respect to cell heterogeneity. In reality, only a small subpopulation of migratory and invasive cells inside the primary tumor is responsible for escaping and initiating dissemination and metastasis. When whole tissue is used for molecular profiling, the expression pattern of these cells is masked by the majority of the non-invasive tumor cells. Therefore, little information is available about the crucial early steps of the metastatic cascade: migration, invasion and entry of tumor cells into the systemic circulation. Method: In the past, we have developed an in vivo invasion assay which can capture specifically the highly motile tumor cells in the act of migrating inside living tumors (Wyckoff et al., 2004, Cancer Research). Here, we used this assay in orthotopic xenografts of human MDA-MB-231 breast cancer cells to selectively isolate the invasive cell subpopulation of the primary tumor. We then performed microarray analysis to compare the gene expression profile of these invading tumor cells to the average primary tumor cells. In this way, we derived a gene signature specific to breast cancer migration and invasion in vivo. Each sample of invasive (INV) and average primary tumor cells (APTC) was pooled from two tumor-bearing mice. RNA was extracted, made into cDNA, then amplified with the Clontech SMART amplification kit. Human reference RNA (Clontech) was amplified with identifical protocol. Each sample was then hybridized in a 28K Human cDNA microarray chip, custom printed from Albert Einstein College of Medicine (http://microarray1k.aecom.yu.edu/). Four replicates were used per group (Invasive vs. Average Primary Tumor).

ORGANISM(S): Homo sapiens

SUBMITTER: Patsialou Antonia

PROVIDER: S-ECPF-GEOD-37733 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ?50% of ER?-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ER?-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ER?-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ER?-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ER?-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies.

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Human breast cancer invasion signature

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