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

Abstract

As a downregulator of the Wnt signaling pathway, SFRP1 is involved in several components of the age-related lobular involution process such as inflammation, apoptosis, and adipogenesis. Because microcalcifications are associated with inflammation, we aimed to demystify the cross talk between SFRP1, inflammatory markers, and microcalcifications by assessing SFRP1 expression (immunohistochemistry) in a cohort of 162 women with different degrees of lobular involution. SFRP1 expression was inversely associated with the degree of lobular involution (OR = 0.84; p-value < 0.01). SFRP1 expression, age at mastectomy, and waist circumference taken together predicted the degree of lobular involution (AUC = 78.1). This predictive model was best in patients with microcalcifications (AUC = 81.1) and in parous women (AUC = 87.8). SFRP1 expression was correlated with leptin (rho = 0.32), TNF-α (rho = 0.21), and IL-6 (rho = 0.21) expression by epithelial cells (all p-values <0.001). SFRP1 expression was lower in nulliparous women with involuted breast tissue compared with parous women with involuted breast tissue (Δmean = −2.31; p-value < 0.01) and was higher in nulliparous women with microcalcifications compared with nulliparous women without microcalcifications (Δmean = 2.4; p-value < 0.05). In this study, we highlighted two SFRP1-based predictive models for incomplete lobular involution and the development of microcalcifications and identified two distinct inflammatory profiles associated with age-related lobular involution in parous and nulliparous women.

TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

“…TMAs were constructed from the FFPE mastectomy blocks containing BC tissue samples as previously described [ 16 ].…”

Breast Cancer and Microcalcifications: An Osteoimmunological Disorder?

“…Consequently, by activating the Wnt signaling pathway, they also observed a decrease of bone resorption combined with an induction of osteoblast mineralization [ 30 ]. In breast, SFRP1 expression is higher during age-related lobular involution and in presence of microcalcifications compared with patients completely involuted and without microcalcification, respectively [ 90 ]. Interestingly, the incidence of RA in breast cancer patients is lower compared with patients without breast cancer after adjustment for age, comorbidities and breast cancer treatments [ 31 ].…”

“…SFRP1 is a good predictor of the degree of lobular involution and its expression is higher in presence of microcalcifications. Moreover, SFRP1 expression is lower in involuted nulliparous women compared with involuted non-nulliparous women suggesting that the first lobular involution is different from the others [ 90 ]. This is particularly important to consider as lower expression of SFRP1 in breast tissue is largely associated with breast cancer development and poor prognosis [ 134 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ].…”

“…Because intermittent PTH is involved in osteoblastogenesis, it is crucial to interrogate the possibility that MSCs and breast cancer cells with mesenchymal characteristics could also develop an osteoblast-like phenotype resulting in hydroxyapatite production. Furthermore, if PTH is responsible for Wnt signaling pathway activation [ 239 ], it is crucial to examine the impact of teriparatide on involuted breast tissue that does not express SFRP1 [ 90 ], a Wnt signaling pathway antagonist. In absence of such a negative regulator, it is plausible that the overactivation of the pro-proliferative Wnt signaling pathway could result in breast hyperplasia.…”

Role of Secreted Frizzled-Related Protein 1 in Early Breast Carcinogenesis and Breast Cancer Aggressiveness

“…In another study, our group demonstrated that SFRP1 was largely expressed in non-involuted breast epithelial tissue, while it dramatically decreased after perimenopausal lobular involution completion in nulliparous women. Furthermore, we observed that SFRP1 expression was also associated with the presence of microcalcifications in breast tissue, once more in nulliparous women specifically [ 23 ]. However, in the absence of well-characterized models of lobular involution and microcalcification development in both nulliparous and multiparous mammalians, the knowledge regarding SFRP1 regulation through pregnancy and hydroxyapatite (HA) microcalcifications remains unsubstantial.…”