Breast Cancer Xenografts In Nude Mice Research Articles

A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes-Associated Breast Cancer.

Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes‐associated BC. This paper aims to understand the fundamental mechanisms of diabetes‐induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF‐κB inhibitor (NF‐κBi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB‐2 has been identified by structure‐based virtual screening. A triple combination of metformin, CB‐2, and trabectedin, a drug that impedes NF‐κB signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell‐killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG‐induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF‐κBi is a promising cancer therapy, especially for diabetes‐associated BC.

GDNF induces RET-SRC-HER2-dependent growth in trastuzumab-sensitive but SRC-independent growth in resistant breast tumor cells.

We investigated the role of glial cell line-derived neurotrophic factor (GDNF) in compensating trastuzumab (TZMB)-induced apoptosis in HER2+ breast cancer (BC) cells using xenograft tumors. We generated BC xenografts in nude mice using samples from three patients selected based on their HER2 status and response to TZMB therapy. TZMB treatment resulted in shrinkage of the HER2+ TZMB-sensitive xenograft tumor but not the HER2- or HER2+ TZMB-resistant ones. GDNF neutralized TZMB activity and induced growth in all tumors. Three distinct cell lines were derived from these tumors and named, respectively, TZMB-sensitive (TSTC), HER2- (HNTC), and TZMB-resistant (TRTC). Over 50% of TRTC but 1% of TSTC cells expressed CD44, whereas 84% of TSTC were CD24+ compared to only 1% of TRTC, despite comparable levels of HER2 detected in both. TZMB induced profound morphological changes toward apoptosis in TSTC but not in TRTC or HNTC. However, GDNF significantly compensated TZMB-mediated TSTC cell loss and promoted growth by 37 and 50%, respectively, in TSTC and TRTC. Inhibition of SRC by Saracatinib (SARC) blocked GDNF function and accelerated TZMB-mediated cell death in TSTC, but GDNF continued promoting TRTC growth. These changes paralleled with expression levels of the key molecules involved in growth and apoptosis. Collectively, we found in our xenograft samples that firstly SRC mediates GDNF pro-survival functions by bridging RET-HER2 crosstalk in TZMB-responsive BC tumors. Secondly, SARC-TZMB interactions can synergistically eradicate such tumor cells; and thirdly, GDNF can support antibody resistance by acting independent from SRC in tumors with poor HER2 response to TZMB therapy.

Abstract P4-07-05: MEDI3379, an antibody against HER3, is active in HER2-driven human breast tumor models

Abstract HER3 (ERBB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Unlike the other HER family members, HER3 lacks intrinsic tyrosine kinase activity and therefore needs to form heterodimers with EGFR, HER2 or other kinase-proficient RTKs to be functionally active. Dimerization is induced by overexpression of EGFR or HER2 in a ligand-independent (LI) manner. In this process HER3 acts as a driver in divergent cancer types including HER2-positive breast cancer (BC) via induction of the PI3K-AKT pathway. Alternatively, heregulin (NRG1/HRG), the major HER3 ligand, induces a conformational shift in HER3 which leads to dimer formation with a partner RTK in a ligand-dependent (LD) manner. We have developed an antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple breast cancer cell lines. We observed effective suppression of constitutive pHER3 and pAKT with MEDI3379, leading to anti-proliferation effects in cell culture models. Preclinical evaluation of MEDI3379 demonstrated antitumor activity in several orthotopic BC xenografts in nude mice which did not express HRG. For example, the BC xenograft model BT474 with amplified HER2 responded to MEDI3379 (65% dTGI). In conclusion, our findings with targeting of HER3 in mouse models support continued development of MEDI3379 for cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-05.