Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

Julia Calvo,Timothy M Thomson,Pedro L Fernández,Lourdes Sánchez-Cid,Juan José Lozano,Montserrat Muñoz,William B Coleman

doi:10.1371/journal.pone.0078097

Abstract

Lymph node involvement is a major prognostic variable in breast cancer. Whether the molecular mechanisms that drive breast cancer cells to colonize lymph nodes are shared with their capacity to form distant metastases is yet to be established. In a transcriptomic survey aimed at identifying molecular factors associated with lymph node involvement of ductal breast cancer, we found that luminal differentiation, assessed by the expression of estrogen receptor (ER) and/or progesterone receptor (PR) and GATA3, was only infrequently lost in node-positive primary tumors and in matched lymph node metastases. The transcription factor GATA3 critically determines luminal lineage specification of mammary epithelium and is widely considered a tumor and metastasis suppressor in breast cancer. Strong expression of GATA3 and ER in a majority of primary node-positive ductal breast cancer was corroborated by quantitative RT-PCR and immunohistochemistry in the initial sample set, and by immunohistochemistry in an additional set from 167 patients diagnosed of node-negative and –positive primary infiltrating ductal breast cancer, including 102 samples from loco-regional lymph node metastases matched to their primary tumors, as well as 37 distant metastases. These observations suggest that loss of luminal differentiation is not a major factor driving the ability of breast cancer cells to colonize regional lymph nodes.

Highlights

Morphological and molecular subtypes of breast cancer have been associated with distinct stages of normal epithelial differentiation [1]
Node-positive primary tumors tended to pair with their matched lymph node metastases rather than form clusters with other node-positive primary tumors (Figure 1A), suggesting that there are no major differences in global gene expression patterns between nodepositive and node-negative primary ductal breast cancer
The dissemination of cells from the primary tumor is first detected in regional lymph nodes, the involvement of axillary lymph nodes being a major prognostic factor in breast cancer [15,17,19]

Summary

Introduction

Morphological and molecular subtypes of breast cancer have been associated with distinct stages of normal epithelial differentiation [1]. Molecular classifications of breast cancer can afford prognostic indicators independent of morphological assessment [5,6,7]. Morphological diagnosis of breast cancer subtypes maintains a prevalent use in many clinical settings mostly because of considerations of cost effectiveness and prompt diagnosis and classification. When combined with selected molecular markers, including the immunohistochemical detection of hormone receptors, HER2 and the proliferation marker Ki67 and copy number quantification of the HER2 locus by FISH, it provides adequate information for the therapeutic management of the tumors, as well as reasonable prognostic value, probably not inferior to molecular classifications for the most common types of breast cancer [8,9,10,11]

Methods

Results

Conclusion