Infrequent Loss of Luminal Differentiation in Ductal Breast Cancer Metastasis

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.

淋巴结受累是乳腺癌的一项核心预后变量。目前尚未明确，驱动乳腺癌细胞定植淋巴结的分子机制，是否与其形成远处转移的能力共享相同的分子基础。在一项旨在识别与导管乳腺癌淋巴结受累相关分子因素的转录组普查研究中，我们发现：通过雌激素受体（estrogen receptor, ER）、孕激素受体（progesterone receptor, PR）及GATA3的表达水平评估的腔面分化表型，在淋巴结阳性原发性肿瘤及配对淋巴结转移灶中仅极少出现丢失。转录因子（transcription factor）GATA3可决定性调控乳腺上皮的腔面谱系特化，在乳腺癌中被广泛认为是肿瘤及转移抑制因子。在初始样本队列中，我们通过定量逆转录聚合酶链反应（quantitative RT-PCR）与免疫组织化学（immunohistochemistry）验证了多数淋巴结阳性原发性导管乳腺癌中GATA3与ER的高表达；在另一项纳入167例经确诊的淋巴结阳性及阴性原发性浸润性导管乳腺癌患者的队列中，我们通过免疫组织化学进一步验证了上述结果，该队列包含102例与原发肿瘤配对的局部区域淋巴结转移灶样本，以及37例远处转移灶样本。上述研究结果表明，腔面分化表型的丢失并非驱动乳腺癌细胞定植局部区域淋巴结的核心因素。