Abstract
BackgroundCancers induce gene expression alterations in stroma surrounding tumors that supports cancer progression. However, it is actually not at all known the extent of altered stromal gene expression enacted by tumors nor the extent to which altered stromal gene expression penetrates the stromal tissue. Presently, post-surgical “tumor-free” stromal tissue is determined to be cancer-free based on solely on morphological normality—a criteria that has not changed in more than 100 years despite the existence of sophisticated gene expression data to the contrary. We therefore investigated the extent to which breast tumors alter stromal gene expression in three dimensions in women undergoing mastectomy with the intent of providing a genomic determination for development of future risk of recurrence criteria, and to inform the need for adjuvant full-breast irradiation.Methods and findingsGenome-wide gene expression changes were determined in histopathologically normal breast tissue in 33 women undergoing mastectomy for stage II and III primary invasive ductal carcinoma at serial distances in three dimensions from the tumor. Gene expression was determined by genome-wide mRNA analysis and subjected to metagene mRNA characterization. Tumor-like gene expression signatures in stroma were identified that surprisingly transitioned to a plastic, normalizing homeostatic signature with distance from tumor. Stroma closest to tumor displayed a pronounced tumor-like signature enriched in cancer-promoting pathways involved in disruption of basement membrane, cell migration and invasion, WNT signaling and angiogenesis. By 2 cm from tumor in all dimensions, stromal tissues were in transition, displaying homeostatic and tumor suppressing gene activity, while also expressing cancer supporting pathways.ConclusionsThe dynamics of gene expression in the post-tumor breast stroma likely co-determines disease outcome: reversion to normality or transition to transformation in morphologically normal tissue. Our stromal genomic signature may be important for personalizing surgical and adjuvant therapeutic decisions and risk of recurrence.
Highlights
Surgical resection of the primary tumor and adjuvant therapy are mainstays of local breast cancer treatment to prevent the growth and metastatic spread of breast cancer [1]
It is well established that cancers induce gene expression alterations in the stroma surrounding tumors that can support cancer progression [6,7,8], Adjacent morphologically normal tissue in the breast post-surgery can harbor pre-neoplastic and neoplastic gene expression changes that are undetectable by histopathology, which in concert with a reactive stromal environment, can give rise to cancer recurrence at primary and distant sites [9]
We show that spatially reproducible and genetically defined stromal regions exist within cancer-free “normal” tissue that displays a gradient from stromal gene expression profiles
Summary
Surgical resection of the primary tumor and adjuvant therapy are mainstays of local breast cancer treatment to prevent the growth and metastatic spread of breast cancer [1]. After local surgical resection and adjuvant therapy, the risk of breast cancer recurrence varies widely, in part based on stage and grade [2,3,4,5], and does not include parameters of tumor-stromal interaction. It is well established that cancers induce gene expression alterations in the stroma surrounding tumors that can support cancer progression [6,7,8], Adjacent morphologically normal tissue in the breast post-surgery can harbor pre-neoplastic and neoplastic gene expression changes that are undetectable by histopathology, which in concert with a reactive stromal environment, can give rise to cancer recurrence at primary and distant sites [9]. We investigated the extent to which breast tumors alter stromal gene expression in three dimensions in women undergoing mastectomy with the intent of providing a genomic determination for development of future risk of recurrence criteria, and to inform the need for adjuvant full-breast irradiation.
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