Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment

Abstract

BackgroundBreast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma–adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of cancer-associated adipocytes differ from those of normal ASCs. Therefore, we investigated an interaction between ASCs and carcinoma cell lines to identify genes associated with ASC invasion of carcinoma cells.Methods3T3-L1 ASC-derived conditioned medium (CM) was treated to measure the proliferation rate of breast cancer cells. To further examine the effect of ASCs, breast cancer cells were cocultivated with either primary human or 3T3-L1 ASCs for migration assays, DNA microarrays, quantitative real-time polymerase chain reactions, and Western blotting experiments. Furthermore, immunoreactivity of S100A7, the most upregulated gene in MCF7, after coculture with ASCs was evaluated for 150 breast cancer tissues to statistically analyze its association with clinicopathological parameters.ResultsWe first confirmed that ASC-derived CM treatment enhanced the cell proliferation rate of MCF7, T47D, SK-BR-3, and ZR-75-1 cell lines, whereas the migration rate of breast cancer cells was promoted by coculture with ASCs. We identified that a small calcium-binding protein, S100A7, was markedly upregulated (by 5.8-fold) in MCF7 cells after coculture with primary human ASCs. Knockdown of S100A7 significantly suppressed ASC-stimulated cell proliferation and migration rate, indicating a possible involvement of S100A7 in the carcinoma–ASC interaction in breast tumors. Furthermore, strong S100A7 immunoreactivity was detected at the invasive front of adipose stromal tissues compared with that at the intratumoral area. The status of S100A7 was also significantly correlated with adverse pathological parameters, and multivariate analysis revealed that S100A7 could be an independent prognostic marker for a poor relapse-free survival rate. Moreover, induction of oncostatin M was detected in cancer-stimulated ASCs, whereas the downstream S100A7 binding proteins/receptor for advanced glycation endproducts were significantly upregulated in correspondence with S100A7 expression in breast cancer cells after coculture with ASCs.ConclusionsThe results of our study suggest that paracrine production of cytokines from ASCs stimulates breast carcinoma cell growth via upregulation of S100A7 expression in breast cancer cell lines.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0863-0) contains supplementary material, which is available to authorized users.

OLFM4, LY6D and S100A7 as potent markers for distant metastasis in estrogen receptor‐positive breast carcinoma

“…and pancreatic 30 cancer, and OLFM4 promoted S-phase transition in proliferation 31 and it was involved in suppressing apoptosis 32 Previous studies demonstrated that S100A7 was highly expressed in the ductal carcinoma in situ (DCIS) with comedo necrosis 20 , and it was involved in transition to invasive breast carcinoma. 12 Very recently, Sakurai et al 14 reported that S100A7 was upregulated by an interaction between breast carcinoma cells and cancer-associated adipocytes, and S100A7 immunoreactivity was significantly associated with histological grade, stage, lymph node metastasis and worse prognosis for relapse-free survival of breast carcinoma, although they did not examine stage IV cases. Our present results are consistent with this report, and it is suggested that S100A7 protein plays an important role in the aggressiveness of ER-positive breast carcinoma, including distant metastasis, and the prognosis of patients.…”

Co-culture With Human Breast Adipocytes Differentially Regulates Protein Abundance in Breast Cancer Cells

“…In vitro studies, using transwell (non-contact) co-culture of mature adipocytes with breast cancer cells, have established that CAA promote breast cancer cell proliferation, viability, migration and invasion (2, 8, [13][14][15][16][17][18]. Recent evidence suggests that cross talk with CAA induces breast cancer cell invasiveness, in part, through metabolic remodelling of the cancer cell, promoting a shift towards increased mitochondrial fatty acid oxidation (17,19).…”

Adipose Stem Cells and Cancer: Concise Review

“…Furthermore, Sakurai et al have demonstrated that crosstalk between these cells within the tumor microenvironment is promoting proliferation and migration. This group found that BCCs stimulate ASCs to secrete cytokines by upregulating the expression of S100A7, a small calcium‐binding protein . Moreover, knockdown of S100A7 significantly suppressed ASC‐stimulated BCC proliferation and migration .…”

“…Studies have investigated the link between increased adiposity and breast cancer by examining the effects that ASCs have on the tumor microenvironment . Groups have shown that secretion of various factors including leptin, insulin‐like‐growth factor 1, and oncostatin M promote breast cancer . It is clear that the secretome of ASCs strongly influences breast cancer behavior.…”