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Characterization of the Chemotherapy-treated PyMT Matrisome

ABSTRACT: Cytotoxic chemotherapy is used to treat many thousands of patients across many cancer types annually. Recent studies have demonstrated that chemotherapy causes systemic response that can be exploited to promote cancer cell survival and dissemination, termed “chemotherapy-induced metastasis. However, there have been no studies investigating how chemotherapy alters the extracellular matrix of breast tumors, or if those changes might help to support metastatic dissemination. Here, we report the first characterization of the chemotherapy-treated breast cancer matrisome using the MMTV-PyMT transgenic mouse model of breast cancer. We identify distinct changes induced by different cytotoxic chemotherapies. In particular, we identify collagen IV as significantly associated with taxane-based chemotherapy treatment. Biological validation confirmed collagen IV as chemotherapy-associated and identified collagen IV-driven Src and FAK signaling as important mediators of invasion in the post-chemotherapy tumor microenvironment.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Breast

DISEASE(S): Breast Cancer

SUBMITTER: Jackson Fatherree

LAB HEAD: Madeleine J Oudin

PROVIDER: PXD032002 | Pride | 2022-03-14

REPOSITORIES: Pride

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Project description:Dipyridamole (DPM) is widely used to prevent strokes and vascular thrombosis. Combination therapy of DPM and antimetabolites has shown synergistic anticancer activity. This study investigated the chemopreventive effects of DPM in the mouse mammary tumor virus promoter driven polyoma middle T oncoprotein (MMTV-PyMT) metastatic breast cancer model. We also investigated the effects of DPM on gene and miRNA expression. Chemopreventive activity was assessed by comparing the time to onset of palpable lesions, primary tumor growth kinetics and the number of lung metastases in transgenic mice treated with DPM or vehicle. Gene expression and microRNA (miRNA) expression profiles of mammary tumor tissues were then analyzed using the Affymetrix GeneChipM-BM-. or miRNA 2.0 arrays. Real-time quantitative PCR (qPCR) was used to confirm changes in gene expression. Treatment with DPM beginning at the age of four weeks delayed the onset of palpable lesions, delayed tumor progression and suppressed lung metastasis. Microarray gene expression analysis identified 253 genes differentially expressed between DPM-treated and control mammary tumors. miRNA expression analysis revealed that 53 miRNAs were altered by DPM treatment. The results indicate that DPM has chemoprevention activity against breast cancer tumorigenesis and metastasis in mice. The array analyses provide insights into potential mechanisms of DPMM-bM-^@M-^Ys chemopreventive effects, involving upregulation of several genes and miRNAs known to suppress cancer growth and/or metastasis and downregulation of genes known to promote cancer. Some of these genes have not been previously studied in breast cancer and may serve as novel molecular targets for breast cancer chemoprevention. MMTV-PyMT+ female mice were randomly divided into a DPM treatment group (n=10 mice, total of 100 glands) and a vehicle (control) group (n=7 mice, total of 70 glands). When mice were four weeks old, when hyperplasia lesions begin to develop in the FVB strain (21), DPM (10 mg/kg) or vehicle was injected IP into the peritoneum of each mouse on a 5 days on/2 days off dosing schedule for a total of 11 weeks (week one=injection one), until mice were 15 weeks of age. Each of the 10 mammary tumors per mouse was monitored until the study end point. A total six breast tumor RNA samples were used for microarray analysis, with three form mice treated with DPM and three from mice treated with vehicle.

			Action	DRS
	120min_Grad_raw.zip	Other
	90min_Grad_raw.zip	Other
	Data_S1.xlsx	Xlsx
	PyMT_tumor_matrisome_chemo.xml	Xml
	checksum.txt	Txt

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Characterization of the Chemotherapy-treated PyMT Matrisome

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