Adipocyte hypoxia promotes epithelial-mesenchymal transition-related gene expression and estrogen receptor-negative phenotype in breast cancer cells

Abstract

The development of breast cancer is linked to the loss of estrogen receptor (ER) during the course of tumor progression, resulting in loss of responsiveness to hormonal treatment. The mechanisms underlying dynamic ERα gene expression change in breast cancer remain unclear. A range of physiological and biological changes, including increased adipose tissue hypoxia, accompanies obesity. Hypoxia in adipocytes can establish a pro-malignancy environment in breast tissues. Epidemiological studies have linked obesity with basal-like breast cancer risk and poor disease outcome, suggesting that obesity may affect the tumor phenotype by skewing the microenvironment toward support of more aggressive tumor phenotypes. In the present study, human SGBS adipocytes were co-cultured with ER-positive MCF7 cells for 24 h. After co-culture, HIF1α, TGF-β, and lectin-type oxidized LDL receptor 1 (LOX1) mRNA levels in the SGBS cells were increased. Expression levels of the epithelial-mesenchymal transition (EMT)-inducing transcription factors FOXC2 and TWIST1 were increased in the co-cultured MCF7 cells. In addition, the E-cadherin mRNA level was decreased, while the N-cadherin mRNA level was increased in the co-cultured MCF7 cells. ERα mRNA levels were significantly repressed in the co-cultured MCF7 cells. ERα gene expression in the MCF7 cells was decreased due to increased HIF1α in the SGBS cells. These results suggest that adipocytes can modify breast cancer cell ER gene expression through hypoxia and also can promote EMT processes in breast cancer cells, supporting an important role of obesity in aggressive breast cancer development.

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Co-culture of obese ASCs with breast cancer cells resulted in increased expression of markers of EMT and metastatic genes (SERPINE1, MMP2, and IL6) [110,111]. Silencing of leptin expression within these obese ASCs prevented this change and, in addition, knockdown of leptin in these breast cancer cells resulted in a reduced tumour volume, decreased number of metastatic deposits, and increased expression of SERPINE1 and MMP2, indicating leptin may have a role in EMT and metastasis [111].…”

The potential role of leptin in tumor invasion and metastasis

“…In an interesting study, MCF-7 cells were co-cultured with SGBS adipocytes (which originated from a patient with Simpson-Golabi-Behmel syndrome, an overgrowth disorder). Gene expression levels of EMT-inducing transcription factors FOXC2 and TWIST1 were increased in the MCF-7 cells while in the SGBS cells hypoxia-inducible factor-1α (HIF-1α), TGF-β, and lectin-type oxidized LDL receptor 1 (LOX1) mRNA levels were increased [32]. …”

Exploiting vulnerabilities of cancer by targeting nuclear receptors of stromal cells in tumor microenvironment

“…The inhibition of AR signaling is followed by alterations in the gene expression of TGF-β via the serine/threonine kinase receptor or TGF-β receptor and its downstream genes such as Smad3 and matrix-metalloproteinase-9, fueling metastatic processes [ 135 ]. Coculturing human Simpson Golabi Behmel Syndrome (SGBS) preadipocyte cells, which are considered to be a representative in vitro model of white preadipocytes, and ER-positive MCF7 breast cancer cells results in the suppression of ERα expression in MCF7 cells [ 136 ]. Cohabitation of preadipocytes and MCF7 cells also significantly enhances the epithelial-mesenchymal transition of MCF7 tumor cells, as documented by overexpression of FOXC2 and TWIST1, and changes in N- and E-cadherin expression [ 136 ].…”

“…Coculturing human Simpson Golabi Behmel Syndrome (SGBS) preadipocyte cells, which are considered to be a representative in vitro model of white preadipocytes, and ER-positive MCF7 breast cancer cells results in the suppression of ERα expression in MCF7 cells [ 136 ]. Cohabitation of preadipocytes and MCF7 cells also significantly enhances the epithelial-mesenchymal transition of MCF7 tumor cells, as documented by overexpression of FOXC2 and TWIST1, and changes in N- and E-cadherin expression [ 136 ]. As a consequence, the expression of HIFα, TGF-β and lectin-type oxidized LDL receptor 1 in SGBS adipocytes are elevated [ 136 ].…”

“…Cohabitation of preadipocytes and MCF7 cells also significantly enhances the epithelial-mesenchymal transition of MCF7 tumor cells, as documented by overexpression of FOXC2 and TWIST1, and changes in N- and E-cadherin expression [ 136 ]. As a consequence, the expression of HIFα, TGF-β and lectin-type oxidized LDL receptor 1 in SGBS adipocytes are elevated [ 136 ]. Both studies have demonstrated that the presence of adipose cells in TME can impact both NR signaling and oncogenic processes in cancer cells.…”