The role of Scara5 in adipogenesis and breast cancer pathogenesis

Suelzu, Caterina Maddalena (2023) The role of Scara5 in adipogenesis and breast cancer pathogenesis. Doctoral thesis, University of East Anglia.

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Affecting millions of people around the world, osteoporosis and bone fragility represent a serious health concern and one of the major threats for elderly people, since the risk of fracture tends to increase with ageing. Similarly, metabolic disorders such as diabetes and obesity stand as major public health problems worldwide. Both bone loss-related diseases and metabolic disorders impact on mesenchymal stromal cells (MSCs) differentiation fate, with adipogenesis favoured at the expense of osteogenesis and resulting in increased adiposity and decreased bone mass. A plethora of factors have been identified as crucial for MSCs lineage differentiation; scavenger receptor class A member 5 (Scara5) recently emerged as a regulator of adipogenesis in vitro. Among its many functions, Scara5 is a ferritin receptor and is reportedly downregulated in human breast cancer (BrCa) cell lines.

Studies conducted on Scara5 -knock out (KO) mice revealed an increased bone mass and a reduced fat deposition. However, bone/fat-related pathologies (i.e. osteoporosis, diabetes) were not influenced by the genetic deletion. In line with these results, Scara5-KO bone marrow MSCs (BMSCs) showed a propensity to become osteoblasts and a reduced ability to differentiate into adipocytes. Mechanistic studies proved that Scara5 deficiency impinged on BMSCs mitochondrial activity during adipogenic differentiation, as well as on murine kidney iron levels. The reduced iron content and adipose tissue deposition also impacted on BrCa development; indeed, Scara5-KO mice developed smaller tumours upon cancer cell injection into the mammary fat pad, as a result of an iron homeostasis perturbation and the consequent reduced fat deposition.

This thesis presents Scara5 as a central regulator of iron homeostasis, MSCs adipogenesis, and breast cancer pathogenesis. Although a reduction in Scara5 has been associated with health problems (i.e. cancer), these findings propose that targeting Scara5 may be useful for developing new therapies to counteract obesity and BrCa pathogenesis.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 13 Mar 2024 16:30
Last Modified: 13 Mar 2024 16:30

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