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							| Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007



	

				
						
 
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																Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007
										

				


				
				
					
					
						
																					
				
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					Vol. 14 No. 12 (2024): December 2024
				
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									Research Articles
							
		



	
		  	 

		
	
		Vitamin A and D3 combinations reduce breast cancer tumor load in a postmenopausal MCF-7 xenograft mouse model in a dose- and time- dependent manner
	


	
	
		

							
					Authors

						
							
								Nishikant A. Raut
							
																																		
	
							
								Temitope O. Lawal
							
																																		
	
							
								Bolanle A. Adeniyi
							
																																		
	
							
								Pinal N. Kanabar
							
																																		
	
							
								Mark Maienschein-Cline
							
																																		
	
							
								Nina S. Los
							
																																		
	
							
								Zarema Arbieva
							
																																		
	
							
								Gail B. Mahady
							
																																		


				
			
																	
					
												DOI:
					

					
						
							https://doi.org/10.31989/ffhd.v14i12.1523
						
					
				
			

						
										
					Abstract

					Introduction: Earlier, we documented that a combination of vitamins A and D3 synergistically inhibited the growth of MCF-7, T48:A18 and SKBR3 breast cancer cells with the best activity seen in the ER+ cell line MCF-7. Transcriptomic analysis of treated MCF-7 cells also showed that the combination significantly upregulated the apoptosis and unfolded protein response canonical pathways, and reduced estrogen signaling.

Objective: This study aimed to explore the impact of increasing vitamin A and D3 dose combinations over time in a postmenopausal model of breast cancer using ovariectomized athymic female mice bearing MCF-7 xenografts and further analyze mechanisms of action in MCF-7 cells using RNA-seq analysis.

Methods: MCF-7 breast cancer cells were grown in culture for the xenograft experiments. Athymic female mice were injected with MCF-7 cells (1 x 10^6 in 100 µl of 50% Matrigel mixed with sterile PBS) via subcutaneous injection. Once the tumors reached an average volume of 100 mm³, the mice were randomly divided into four groups and treated with different vitamin A and D3 combinations. Tumor sizes and mouse body weights were monitored on a biweekly basis. After the treatment period, the mice were euthanized, and the tumors were surgically removed and measured. RNA-seq data from the treated MCF-7 cells were then further evaluated using IPA. 

Results: As compared with controls, treatment with vitamin A (25,000 IU) and vitamin D (10,000 IU) led to a significant reduction in tumor volume >70%, (p < 0.05-0.01) in OVX athymic mice with MCF-7 xenografts as determined by a two-tailed Student T test. Over the treatment period, the tumor volume in mice treated with vitamin A (10,000 IU) and vitamin D (5,000 IU) or vitamin A (25,000 IU) and vitamin D (5,000 IU) also trended downward and was statistically significant using one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test (p<0.05 and p<0.0001, respectively) but was not significant using a two-tailed Student T test. In cultured MCF-7 cells, Ingenuity Pathway Analysis of mRNA-seq data showed that the vitamin A and D combination significantly altered the expression of 101 genes out of 864 in the molecular mechanisms in cancer canonical pathway, downregulating gene expression in the integrin/P13K/Akt/mTOR pathway.

Conclusions: The findings showed that the combination of vitamins A and D3 effectively reduced tumor burden in a postmenopausal MCF-7 xenograft mouse model, with effects that were both dose-dependent and time-dependent. The combination also significantly altered the expression of genes in the molecular mechanisms of cancer canonical pathway in cultured MCF-7 cells. These preclinical data support the use of vitamins A and D3 in the management of estrogen-dependent breast cancers, with the caveat that higher doses and longer treatment periods may be needed to observe anti-tumor effects.

Keywords: Apoptosis, autophagy, breast cancer, cell cycle, integrin, postmenopausal, P13K, tumor load, xenograft





				
			
			

						
																																																																				
						
		


		

						
										
					
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																			2024-12-18
																	

				
							

			
						
										

											
							
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									Vol. 14 No. 12 (2024): December 2024
								
							

						
					
											
							
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								Research Articles
							

						
					
									

			
						
										
					
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