MYC is expressed in the stromal and epithelial cells of primary breast carcinoma and paired nodal metastases

Abstract

Abstract. The MYC oncogene is directly involved in the proliferation, metabolism, progression and distant metastasis of breast cancer. Since metastatic spread to the lymph nodes is often the first indication of propensity for metastatic dissemination, the MYC status in nodal disease may represent a decision-making variable. However, the analysis of MYC expression in stromal cells, namely cancer-associated fibroblasts (CAFs), which are known to play a critical role in cancer progression, remains poorly reported. The aim of this study was to determine the expression of MYC and other markers, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), p53, Ki67, epidermal growth factor receptor (EGFR), phosphorylated AKT (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) by immunohistochemistry in representative samples from 80 patients with ductal infiltrative breast cancer and 43 paired compromised axillary lymph nodes allocated in tissue microarrays (TMAs). The epithelial and stromal components of primary tumors and respective lymph node metastases were separately analyzed. MYC expression (cytoplasmic and nuclear) was a frequent event in the epithelial and stromal components of the primary tumors. The epithelial cells in the nodal metastases exhibited a trend for decreased MYC expression compared to that in the primary tumors (P=0.08) but retained the original status of the primary tumors for all other markers. The stromal cells were uniformly negative for ER, PR, HER2, p53, Ki67 and EGFR. Comparison of the stromas of primary tumors and respective lymph node metastases revealed a reduced frequency of nuclear MYC in 15% of the cases (P=0.003), whereas p-mTOR followed a similar trend (P=0.09). Analyses of the possible correlations among markers revealed that epithelial nuclear MYC was associated with p53 (P=0.048). This is an original study demonstrating a significant proportion of MYC expression (nuclear or cytoplasmic), as well p-mTOR and p-AKT expression, in the epithelial and stromal components of either the primary tumor or the nodal metastases. CAFs expressing MYC may establish an angiogenic microenvironment supporting cancer survival and facilitating colonization at the nodal metastatic site.

MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

“…In the past 20 years, several reports suggest that TAMs are critical players in regulating the “angiogenic switch” and are essential in stimulating tumor angiogenesis and progression [ 29 , 79 , 80 ]. It has also been noted that the up-regulation of MYC was found in cancer-associated fibroblasts (CAFs) and that CAFs can promote tumor angiogenesis by secreting cytokines that recruit endothelial cells to form tumor-associated blood vessels—suggesting that MYC is also important in the regulation of CAFs within tumor microenvironment [ 81 , 82 , 83 ]. Hypoxia is recognized as a major driver of angiogenesis.…”

“…This demonstrates that the increased expression of MYC can be linked with nodal metastases. Fibroblasts expressing MYC act locally at metastatic site and help to facilitate colonization by creating a lymphangiogenic microenvironment to support cancer cells’ survival [ 83 , 99 ]. Moreover, MYC directly regulates several genes related to glucose metabolism (such as Lactate dehydrogenase A), and CAFs were reported to have increased expression of glycolytic enzymes.…”

“…Moreover, MYC directly regulates several genes related to glucose metabolism (such as Lactate dehydrogenase A), and CAFs were reported to have increased expression of glycolytic enzymes. Therefore, cancer cells can use these enzymes to facilitate tumor growth and vascularization [ 83 , 110 , 111 ].…”

Unraveling MYC’s Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance

“…This enhanced vascular network facilitates cancer cell survival and enables the cells’ rapid proliferation. Emerging evidence indicates that MYC upregulation is not limited to cancer cells but also extends to cancer-associated fibroblasts (CAFs) [ 109 ]. CAFs have been shown to play a crucial role in promoting tumor angiogenesis [ 110 , 111 ].…”

Role of c-Myc in lung cancer: Progress, challenges, and prospects

“… 62 c-Myc expression in CAFs has been shown to promote the secretion of cytokines that induce the formation of blood vessels by recruiting endothelial cells. 63 There are other c-Myc induced proteins and non-coding RNAs that promote angiogenesis. The study of Ciribilli and Borlak 64 identified 25 novel target genes of c-Myc in a transgenic mouse model of lung cancer, some of which, such as G-protein couple receptor Adora2B, induced angiogenesis by either inducing VEGF or downregulating negative regulators of HIF-1 α .…”