Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression

Abstract

The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors.

Synthesis of Curcumin Derivatives and Analysis of Their Antitumor Effects in Triple Negative Breast Cancer (TNBC) Cell Lines

“…In fact, SUM 149 is a model of inflammatory breast cancer, a basal-like subtype, while MDA-MB-231 is claudin-low subtype. Other authors observe different responses to drugs between these two cell lines though both are TNBC models [44,45].…”

Ganoderma spp.: A Promising Adjuvant Treatment for Breast Cancer

“…GLE also showed strong cytotoxic effects in the triple negative BC cell lines, SUM-102 and MDA-MB-468, and also on the HER2 overexpressing MDA-MB-435. However, the noncancerous mammary epithelial cells, MCF-10A, were not affected by treatment [ 20 , 21 ]. Furthermore, the effect of GLE has been evaluated in inflammatory breast cancer (IBC), which is the most lethal type of advanced BC and which presents unique characteristics that differentiate it from non-IBCs [ 22 ].…”

“…Furthermore, the effect of GLE has been evaluated in inflammatory breast cancer (IBC), which is the most lethal type of advanced BC and which presents unique characteristics that differentiate it from non-IBCs [ 22 ]. In these studies, GLE significantly affected the viability or proliferation of SUM-149 and KPL-4 IBC cells by proapoptotic effects [ 20 , 21 ]. The authors demonstrated that the regulatory gene expression of cell-cycle progression was affected in SUM-149 IBC cells.…”

“…Studies in IBC also support the anti-invasive effect of GLE. Treatment with GLE inhibited migration and invasion of SUM-149 cells after 24 and 72 h [ 20 , 21 ]. Ganoderic acid, GDNT and GA-Me also reduced BC (MDA-MB-231) cell adhesion to the extracellular matrix protein vitronectin, as well as cell migration and cell invasion [ 32 , 36 , 61 ].…”

G9A performs important roles in the progression of breast cancer through upregulating its targets

“…In particular, inflammatory triple-negative BC, a type of rare and aggressive BC with a significantly poorer 5-year survival rate compared with other types of BC, is believed to mainly be attributed to an abnormal inflammatory response (28,29). Previous studies have considered that the ECM-receptor interaction pathway may be associated with the progression of BC, which could indicate the repeatability of the present study (30,31).…”