R‐spondin‐mediated WNT signaling potentiation in mammary and breast cancer development

Abstract

The mammary gland is a secretory organ, which develops as a network of growing epithelial ducts composed of luminal and basal cells that invade the surrounding adipose tissue through a series of developmental cycles. Mammary stem cells (MaSCs) maintain an accurate tissue homeostasis, and their proliferation and cell fate determination are regulated by multiple hormones and local factors. The WNT pathway plays a critical role in controlling the enormous tissue expansion and remodeling during mammary gland development through the maintenance and differentiation of MaSCs, and its deregulation has been implicated in breast cancer (BC) initiation and progression. The R-spondins (RSPOs) are four secreted proteins that strongly enhance target cell sensitivity to WNT ligands. Moreover, leucine-rich repeat-containing G-protein-coupled receptors (LGRs) 4-6 are considered obligate high-affinity receptors for RSPOs and have been described as stem cell markers. Importantly, elevated RSPO expression has been recently identified in several tumor types from patients, including BC, and it has been reported that they play a significant role in mammary tumor progression in experimental models. In this review, exploring our present knowledge, we summarize the role of the RSPO-LGR axis as a WNT-enhancing signaling cascade in the MaSC compartment and during the normal and neoplastic mammary gland development. In addition, we include an updated expression profile of the RSPOs and their action mediators at the cell membrane, the LGRs, and the ubiquitin-ligases ZNRF3/ RNF43, in different BC subtypes. Finally and based on these data, we discuss the significance of tumor-associated alterations of these proteins and their potential use as molecular targets for detection and treatment of BC.

A Body Shape Index (ABSI), hip index, and risk of cancer in the UK Biobank cohort

“…Furthermore, cancer tissues modulate local cortisol activation‐deactivation enzymes toward increased local cortisol production, thus inhibiting tumor‐specific cytotoxic T‐cells and facilitating tumor growth 46 . In addition, major genes associated with body shape code signaling factors involved in cell differentiation, proliferation, apoptosis, migration, and angiogenesis, 47,48 which may promote region‐specific cancer growth and have been associated with various cancers 49,50 . Indirect links are also possible.…”

“… 46 In addition, major genes associated with body shape code signaling factors involved in cell differentiation, proliferation, apoptosis, migration, and angiogenesis, 47 , 48 which may promote region‐specific cancer growth and have been associated with various cancers. 49 , 50 Indirect links are also possible. For example, inactivation of melanocortin receptors in mouse knockout models or in humans with genetic polymorphisms has been associated with abdominal obesity and metabolic syndrome, 51 but could also be associated with lower risk of melanoma, which is linked to the activation of melanocortin receptors.…”

GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer

“…RSPO3 shows differential expression in adipose depots, with the highest expression in visceral, intermediate in abdominal subcutaneous and lowest in gluteal subcutaneous adipose tissue 15 . RSPO3 additionally promotes angioblast specification and vascular development 16 , plays a key role throughout life in maintaining the structural zonation and the replenishment of damaged cells in the adrenal glands 17 , regulates the renewal and differentiation of stem cells 18 , and contributes to cancer development and progression 19 , 20 . Genetic variants in the RSPO3 locus associated with abdominal obesity have additionally been associated with dyslipidaemia 21 , thus relating the RSPO3 gene to the metabolic syndrome.…”

RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis

“…Human genetic studies revealed that RSPO1 is critical for ovarian development ( 51 ), and RSPO2 mutation leads to tetra-amelia syndrome including lung aplasia and a lack of limbs ( 18 ), while RSPO4 is necessary for human nail formation ( 52 ). In breast tumors, RSPO2 and RSPO3 were first identified as being involved in BCa initiation, proliferation, epithelial-mesenchymal transition, and metastasis ( 53 ). The expression of RSPO2 and RSPO4 is increased in basal and metaplastic tumors ( 54 ), while the highest levels of RSPO3 expression were detected in basal BCa ( 55 ).…”