Research Article: A genomic ruler to assess oncogenic transition between breast tumor and stroma

Date Published: October 16, 2018

Publisher: Public Library of Science

Author(s): Shubhada Dhage, Amanda Ernlund, Kelly Ruggles, Deborah Axelrod, Russell Berman, Daniel Roses, Robert J. Schneider, Abdelilah Aboussekhra.


Cancers 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.

Genome-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.

The 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.

Partial Text

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 [2–5], 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 [6–8], 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]. Detecting occult disease through genetic approaches would allow for a more informed understanding and redefinition of a “clean” surgical margin, and might inform personalized targeted adjuvant therapy to genetically aberrant but histopathologically normal stroma based on individual tumor-stromal characteristics.

It has long been debated whether excising larger regions of non-cancerous tissue (the surgical margin) for invasive breast actually impacts on the rate of ipsi-lateral breast cancer recurrence [43]. Consensus guidelines regarding the adequate surgical margin in breast and other surgeries are based solely on histopathologic parameters and do not integrate information regarding the activation state of, or gene expression in the surrounding stroma [34, 44]. There are no surgical or treatment guidelines that include parameters of the tumor microenvironment.




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