DEFINING THE MOLECULAR IMPACT OF TOTAL DIET REPLACEMENT IN ENDOMETRIAL AND BREAST TISSUES

Abstract

Background: Obesity and overweight are strong and modifiable risk factors for postmenopausal breast and endometrial cancers. The PRevention of Breast and Endometrial cancer using Total Diet Replacement (PRoBE-TDR) study aimed to examine the effect of TDR-induced weight loss on normal breast and endometrial cell proliferation, breast progenitor cell activity and cancer risk biomarkers in high-risk women. Methods: PRoBE-TDR was a prospective, non-blinded, randomised controlled trial in pre-menopausal women with obesity at increased risk of breast and/or endometrial cancer. Randomisation was 2:1 to either immediate 12-month TDR-based weight loss programme or delayed intervention (control) group. Biopsies of the breast and endometrium were assessed at baseline and after 12 weeks in both groups for proliferation (Ki67) and gene expression (RNA sequencing) and breast samples for progenitor cell activity (mammosphere assay) and cellular hierarchy (by flow cytometry). Anthropometric measurements and blood sampling for cancer risk biomarkers (fasting glucose, insulin, HOMA-IR, fasting lipids, CRP, IL-6, TNF-α, leptin and adiponectin) were obtained at baseline and then 12-weekly for the duration of the study. Results: Forty-seven women were randomised to immediate (n=30) or delayed TDR (n=17). Significant weight loss was observed with TDR; median absolute weight reduction was -9.9kg (IQR -12.8 to -7.0, P 0.99) in the control group. Additionally, breast luminal progenitor cells were reduced from median 21.6% to 9.0%, a median absolute difference of -9.6% (95% CI -19.5 to 0.58, P=0.04). No significant differences in any other sub-populations were seen. RNA sequencing analysis demonstrated downregulation of extra-cellular matrix(ECM)-receptor interaction, tight junctions, Hippo signalling and ErbB signalling pathways in breast tissue with >10% weight loss. Within endometrial tissues, immune system pathways were downregulated. Conclusion: This is the first study to simultaneously assess the molecular impact of weight loss using TDR in both breast and endometrial tissues. We have demonstrated downregulation of pathways associated with cancer risk in both tissues. TDR achieved statistically and clinically significant weight loss and for the first time, we have demonstrated reduced progenitor cell activity in the normal human breast as a result. Although TDR-induced weight loss may reduce breast cancer risk in women with obesity, further validation work is required to quantify the alteration in gene expression and large scale cohort studies are required to ascertain the longer term impact of the reductions observed within this study.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Tony Howell (Supervisor), Michelle Harvie (Supervisor), Sacha Howell (Supervisor), Robert Clarke (Supervisor) & Emma Crosbie (Supervisor)