The potential for the bioactive lipid DHA to be part of breast cancer treatment, a journey from bench to bedside

Catherine Field, PhD
Professor
Department of Agriculture, Food and Nutritional Science
Faculty of Agricultural, Life and Environmental Science
University of Alberta

This conference is organized by May Faraj, PhD. It is part of the 2022-2023 IRCM conference calendar.

In person: 
IRCM Auditorium
110, avenue des Pins O, H2W 1R7 Montreal
Wearing a mask is mandatory at all times

Online:
Zoom Link : https://zoom.us/j/95269762104
ID : 952 6976 2104
Code : 476372

IRCM conferences are set to occur under a hybrid format. However, please note that last-minute changes to online-only lectures may occur due to unforeseen circumstances. We invite you to visit this webpage again a few days before attending.

About the conference:
Breast cancer is the most frequently diagnosed and the second leading cause of cancer related death in Canadian women. Docosahexaenoic acid (DHA) is an n-3 long chain polyunsaturated fatty acid (LCPUFA) that has shown efficacy in reducing breast cancer cell growth, how it improves the efficacy of standard chemotherapy and the mechanisms involved have not been established. The overall objective of our research program is to determine the efficacy of DHA in the treatment of breast cancer. In a series of in vitro and in vivo experiments with immortalized BC cells, we sought to establish the efficacy and mechanisms for how pre-treatment of BC cells with DHA improves the action of chemotherapy. First, we determined that DHA is differentially incorporated into whole cell and lipid raft membranes of breast cancer cell lines, with higher incorporation occurring in MDA-MB-231 triple negative breast cancer compared to estrogen receptor positive MCF-7 cells. Doxorubicin (DOX) chemotherapy treatment did not alter this incorporation. Microarray analysis indicated that DHA+DOX treated MDA-MB-231 cells had upregulated expression of apoptosis genes (RIPK1, Caspase-10) and down regulated cell cycle gene expression (Cyclin B1, WEE1, Cdc25C, all P<0.05). Mice fed a 2.8% w/w DHA diet and treated with 5 mg/kg DOX had 50% smaller MDA-MB-231 tumours compared to control (0% DHA) fed mice and increased expression of apoptotic proteins (Caspase-10 and Bid) combined with decreased cell cycle proteins (Cyclin B1 and Cdc25c, P<0.05). Immortalized cell lines do not accurately represent the heterogenicity seen in human tumours, therefore patient derived xenografts (PDX’s) represent a new model in which to study the efficacy of treatments.  Mice bearing MAXF574 TNBC PDXs fed a 3.8% w/w DHA diet in combination with 5 mg/kg docetaxel (TXT) had a 57% reduction in tumour weight compared to mice fed a control diet (P<0.004) and a 64% reduction compared to control diet +TXT (P<0.01). DHA+TXT resulted in higher expression of proapoptotic proteins: RipK1 and Bid, lower expression of Ki67 proliferation marker, Bcl-2 and Parp and increased cell cycle arrest compared to control or Control+TXT mice (P<0.05). Both DHA resulted in increased necrotic tissue and decreased NFϏB protein expression compared to control tumours, however only HDHA+TXT had increased expression of necroptosis related proteins: RIPK1, RIPK3 and MLKL (P<0.05). From here we translated this to determine the efficacy of supplementing 4.4 g/ day DHA in women undergoing neoadjuvant chemotherapy. A randomized, placebo-controlled trial received ethics and Health Canada approval and 76 women have been enrolled (enrollment ending in July 2023).  Women entering the study had an average age of 52 years with a BMI=28.5±1.0. Half the women were post-menopausal and at baseline, women had 2.3±0.1% DHA content in plasma phospholipids. We will not have completed the trial until mid-Oct but we will have some data to share. This study enabled us to also look at the effect of DHA on immune function.  In summary, our data provided strong pre-clinical evidence of efficacy of DHA in combination with chemotherapeutics in reducing BC cell growth. The mechanisms of action through which DHA works include increased apoptosis, necroptosis and cell cycle arrest and decreased cellular proliferation. Collectively the evidence obtained from these studies details the role of DHA in a neoadjuvant setting that we hypothesize will be confirmed in the clinical trial.

About Catherine Field, PhD:
Dr. Catherine Field is a Registered Dietitian who began her academic career at the University of Alberta in 1991. Her research program centers on the effect of nutrition on the development of the immune system and the role of specific fatty acids in the treatment of breast cancer. She is a CRC Tier 1 Chair in Human Nutrition and Metabolism and a fellow of the Canadian Academy of Health Sciences as well as the Canadian Nutrition Society. She has published over 290 peer-reviewed publications and has been invited to present keynote lectures more than 210 times around the world.

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