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

Alisson Clemenceau; Aurélie Lacouture; Juliette Bherer; Geneviève Ouellette; Annick Michaud; Étienne Audet-Walsh; Caroline Diorio; Francine Durocher

doi:10.3390/cancers15082251

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

Cancers (Basel). 2023 Apr 12;15(8):2251. doi: 10.3390/cancers15082251.

Authors

Alisson Clemenceau^{1

2}, Aurélie Lacouture^{1

2}, Juliette Bherer^{1

2}, Geneviève Ouellette^{1

2}, Annick Michaud^{2

3}, Étienne Audet-Walsh^{1

2}, Caroline Diorio^{2

3}, Francine Durocher^{1

2}

Affiliations

¹ Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada.
² Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada.
³ Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada.

Abstract

A human transcriptome array on ERα-positive breast cancer continuum of risk identified Secreted Frizzled-Related Protein 1 (SFRP1) as decreased during breast cancer progression. In addition, SFRP1 was inversely associated with breast tissue age-related lobular involution, and differentially regulated in women with regard to their parity status and the presence of microcalcifications. The causal role of SFRP1 in breast carcinogenesis remains, nevertheless, not well understood. In this study, we characterized mammary epithelial cells from both nulliparous and multiparous mice in organoid culture ex vivo, in the presence of estradiol (E2) and/or hydroxyapatite microcalcifications (HA). Furthermore, we have modulated SFRP1 expression in breast cancer cell lines, including the MCF10A series, and investigated their tumoral properties. We observed that organoids obtained from multiparous mice were resistant to E2 treatment, while organoids obtained from nulliparous mice developed the luminal phenotype associated with a lower ratio between Sfrp1 and Esr1 expression. The decrease in SFRP1 expression in MCF10A and MCF10AT1 cell lines increased their tumorigenic properties in vitro. On the other hand, the overexpression of SFRP1 in MCF10DCIS, MCF10CA1a, and MCF7 reduced their aggressiveness. Our results support the hypothesis that a lack of SFRP1 could have a causal role in early breast carcinogenesis.

Keywords: ESR1; SFRP1; Secreted Frizzled-Related Protein 1; atypical ductal hyperplasia; breast cancer; estrogen receptor; lobular involution; organoids; triple-negative breast cancer.

Grants and funding

This research was funded by the Endocrinology and Nephrology axis of the CHU de Québec Université Laval. A.C. and A.L. hold a Formation de doctorat scholarship from the Fonds de recherche du Québec–Santé (FRQS). A.L. received scholarships from the Fondation du CHU de Québec-Université Laval, the Fonds de recherche et d’enseignement de la Faculté de médecine–Université Laval and the Citoyenne du monde scholarship from Université Laval. J.B. received a scholarship from the Canadian Institutes of Health Research.