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Transcription profiling of human pre-malignant breast cancer samples

ABSTRACT: Enlargement of normal terminal duct lobular units (TDLUs) by hyperplastic columnar epithelial cells is one of the most common abnormalities of growth in the adult female human breast. These hyperplastic enlarged lobular units (HELUs) are important clinically as the earliest histologically identifiable potential precursor of breast cancer. The causes of the hyperplasia are unknown but may include estrogen-simulated growth mediated by estrogen receptor alpha, which is highly elevated in HELUs and may be fundamental to their development. This study used DNA microarray technology and RNA from microdissected pure epithelial cells to learn more about changes in gene expression and molecular pathways associated with the development of HELUs from TDLUs Experiment Overall Design: Samples for the microarray studies were derived from 8 formalin-fixed paraffin-embedded tissue (FFPET) biopsies containing paired normal TDLUs and well-developed HELUs from non-cancerous adult female human breasts obtained within the past 3 years. Populations of nearly pure (>95%) epithelial cells were isolated from the TDLUs and HELUs in each biopsy (approximately 25,000 cells/sample) by laser capture microdissection (LCM)

ORGANISM(S): Homo sapiens

SUBMITTER: Lee S

PROVIDER: S-ECPF-GEOD-7377 | biostudies-other | 2007 Jul

REPOSITORIES: biostudies-other

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Project description:Histological grading of breast cancer defines morphological subtypes informative of metastatic potential, although not without considerable inter-observer disagreement and clinical heterogeneity particularly among the moderately differentiated grade II (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade I (G1) and grade III (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with moderately differentiated disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable to that of lymph node status and tumor size. When incorporated into the Nottingham Prognostic Index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low and high grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression. Three separate breast cancer cohorts were analyzed: 1) Uppsala (n=249), 2) Stockholm (n=58), 3) Singapore (n=40). The Uppsala and Singapore data can be accessed here. The Stockholm cohort data can be accessed at GEO Series GSE1456. Experiment Overall Design: All tumor specimens were assessed on U133 A and B arrays.

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Transcription profiling of human pre-malignant breast cancer samples

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