Gene Expression Profiles Associated with the Presence of a Fibrotic Focus and the Growth Pattern in Lymph Node–Negative Breast Cancer

Abstract Background: Specific gene expression profiles correlate with recurrence of breast cancer in lymph node-negative patients. In contrast, insufficient knowledge is available regarding tumor-specific gene expression in patients with lymph node metastasis before surgery. Furthermore, such patients experience cumulative incidences of relapse greater than 50%. Methods: Sections of formalin-fixed paraffin embedded (FFPE) were prepared from breast tumors of 37 patients who were followed for at least 5 years. FFPE samples of patients with recurrent ductal breast cancer (n = 25) and 12 FFPE samples of such patients without recurrence were subjected to microarray analysis to identify gene expression profiles specifically associated with positive lymph nodes confirmed during surgery that were accompanied by lymphocytic invasion. Immunohistochemistry was employed to determine the estrogen receptor (ER) status of cancer tissues. All patients were administered tamoxifen after surgery, and this treatment continued for more than 5 years, or until cancer recurred. This strategy eliminated interactions between different therapeutics as potential confounding factors that influenced patients' outcomes.Results: Sixteen genes were expressed at significantly higher levels in patients with ER-positive (+) breast cancer with recurrence compared with those without recurrence. Gene Set Enrichment Analysis of The Kyoto Encyclopedia of Genes and Genomes (KEGG) identified 73 genes encoding olfactory receptors included in the “Olfactory transduction” pathway that were enriched in the ER+ recurrence group (FDR P < 0.05). The KEGG “Histidine metabolism” and “Retinol metabolism” pathways were enriched in patients with ER-negative (–) breast cancer with recurrence (FDR P < 0.05). Conclusions: The present study is the first, to our knowledge, to identify 16 genes encoding proteins with diverse functions as well as 73 genes encoding olfactory receptors. These genes may serve as presurgical biomarkers for the recurrence of ER+ breast cancers with lymph node metastasis before surgery. These findings identify potential therapeutic targets for preventing cancer relapse, particularly after lymph nodes metastasis.

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The Presence of a Fibrotic Focus Is an Independent Predictor of Early Metastasis in Lymph Node-Negative Breast Cancer Patients

The American Journal of Surgical Pathology ◽

10.1097/00000478-200112000-00016 ◽

2001 ◽

Vol 25 (12) ◽

pp. 1557-1558 ◽

Cited By ~ 28

Author(s):

Cecile Colpaert ◽

Peter Vermeulen ◽

Eric Van Marck ◽

Luc Dirix

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Patients ◽

Independent Predictor ◽

Breast Cancer Patients ◽

Node Negative ◽

Early Metastasis ◽

Fibrotic Focus ◽

Node Negative Breast Cancer

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Limited Clinical Utility of Prognostic Gene Expression Profiles in Grade 3 Node-Negative Early Stage Breast Cancer.

10.1158/0008-5472.sabcs-09-103 ◽

2009 ◽

Cited By ~ 4

Author(s):

P. Bedard ◽

M. Ignatiadis ◽

B. Haibe-Kains ◽

S. Loi ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Clinical Utility ◽

Early Stage ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Early Stage Breast Cancer ◽

Node Negative ◽

Prognostic Gene ◽

Grade 3

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Down-regulation of bbc3, flt1 and gstm3 is associated with lymph node metastases in breast carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21171 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21171-21171 ◽

Cited By ~ 1

Author(s):

E. Saavedra Villarroel ◽

J. Gutierrez ◽

C. Risueño ◽

P. Gonzalez ◽

L. Solis ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Lymph Node ◽

Axillary Lymph Node Metastasis ◽

Axillary Lymph ◽

Down Regulation ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Beta 2 ◽

Beta 2 Microglobulin

21171 Background: Background: Axillary lymph node metastasis is the most significant marker for the pathologic staging of breast cancer. However a proportion of lymph node-negative breast cancer will develop metastatic disease. Therefore, molecular markers of invasion in these patients are needed Methods: We selected 10 primary breast cancer cases, 5 lymph node-negative (T1N0) and 4 lymph node-positive (T1N1). In these cases we searched for gene expression of 8 genes (bbc3, cegp1, fgf18, flt1, cffm4, gstm3, hec, tgfb3) selected from previous studies as a good candidates for metastasis prediction. A quantitative Real-Time PCR was performed using beta-2- microglobulin gene expression to normalized gene expression of each gene. The expression average of beta-2-microglobulin was 303,291 among T1N0 and 342,533 among T1N1 cases (ratio 0.88). The expression average of these 8 genes was 2.11 and 0.002 at T1N0 and T1N1 respectively (ratio 1,055). At least 3 genes were significantly down-regulated in T1N1 (bbc3, flt1, gstm3) in comparison with T1N1 breast carcinomas Results: Computational analysis reveals that these 3 genes (bbc3, flt1, gstm3) contain CpG islands in their promoter regions. Although preliminary data, we found group of genes that are down-regulated in T1N1 tumor Conclusions: The finding that these genes are epigenetically regulated, suggest that could be a good candidates for metastasis prediction, by methylation approach (MethyLight System). Since this down-regulation occurs in primary tumor, the analysis of these genes might be useful to predict metastasis in lymph node-negative breast cancer. No significant financial relationships to disclose.

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