Role of Secreted Frizzled-Related Protein 1 in Early Mammary Gland Tumorigenesis and Its Regulation in Breast Microenvironment

Abstract

In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution. Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the literature. Indeed, the lack of SFRP1 is associated with both tumor development and patient prognosis. Considering the increased risk of breast tumor development associated with incomplete mammary gland involution, it is crucial to demystify the “grey zone” between physiological age-related involution and tumorigenesis. In this review, we explore the functions of SFRP1 involved in the breast involution processes to understand the perturbations driven by the disappearance of SFRP1 in mammary tissue. Moreover, we question the presence of recurrent microcalcifications identified by mammography. In bone metastases from prostate primary tumor, overexpression of SFRP1 results in an osteolytic response of the tumor cells. Hence, we explore the hypothesis of an osteoblastic differentiation of mammary cells induced by the lack of SFRP1 during lobular involution, resulting in a new accumulation of hydroxyapatite crystals in the breast tissue.

The Importance of Breast Adipose Tissue in Breast Cancer

“…The importance of breast adipose tissue in proper breast involution was also indicated in the study on Secreted Frizzled Related Protein 1 (SFRP1). SFRP1 is a known adipokine secreted by adipocytes, and it plays a role in adipogenesis, inflammation and apoptosis [37][38][39] processes that are all of significant importance in breast involution (Figure 1). Furthermore, SFRP1 overexpression was observed in the post-lactation period [40] indicating its role in involution.…”

“…The site of involution is enriched with TGFβ, VEGF, TNFα and IL6 [208], which have all been shown to promote cancer, and are also secreted by breast adipose tissue. On the other hand, a review from our group has highlighted that there could be a possible link between the post-lactation overexpression of SFRP1 and complete involution [37], as mice lacking expression of SFRP1 display a breast morphology that is similar to mid-pregnancy mice [41]. This could also suggest a protective role of breast adipose tissue against BC.…”

Secreted Frizzled-Related Protein 1 as a Biomarker against Incomplete Age-Related Lobular Involution and Microcalcifications’ Development

“…SFRP1 seems to be a crucial player in all steps of the age-related lobular involution process [ 8 , 9 , 10 ]. Age-related lobular involution, a physiological breast atrophy described as a natural protective process against breast tumorigenesis [ 11 , 12 , 13 ], is composed of three known phenomena: Inflammation, apoptosis, and adipogenesis [ 14 , 15 ].…”

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

“…Previously, it is reported that overexpression of ALDH1A1, an isozyme linked to CSCs and EMT, is related to different poor prognostic outcomes [ 38 , 39 , 40 ]. Furthermore, a secreted frizzled-related protein 1 (SFRP1) is known to be responsible for hyperplasia [ 41 ], and thus, lack of SFRP1 is accompanied by both tumor development and poor prognosis for breast cancer [ 41 ]. In our study, we found that both ALDH1A1 and SFRP1, two commonly important genes for EMT and CSCs, are capable of predicting the overall survival rates for breast cancer.…”