A subpopulation of CD44+/CD25-/CD100+ cells contributes to the development of basal epithelial-like metaplastic breast cancer in adiponectin-deficient MMTV-PyVT mice

Abstract

Adiponectin is a protein exclusively secreted by adipose tissue and possesses potent insulin-sensitizing, anti-inflammatory, anti-atherogenic and anti-tumorigenic activities. Its expression and production are inversely associated with breast cancer risk both in pre- and postmenopausal women. Previous studies have demonstrated that adiponectin exerts the antitumorigenic activity by inducing apoptosis and arresting cell cycle progression in human breast cancer MDA-MB-231 cells through GSK3β/β-catenin signaling pathway. Administration of this protein reduces tumor growth of MDA-MB-231 xenografts and decreases lung metastasis in nude mice. Reduced or complete loss of adiponectin expression promotes the development of a distinct basal epithelial-like subtype of mammary tumor in MMTV-PyVT mice. Despite this evidence, the mechanisms underlying the anti-breast cancer activity of adiponectin remain poorly understood.

The survival and growth of mammary epithelial carcinoma are critically dependent on the interactions with the neighboring cells of tumor stroma. Breast cancers grow in the anatomical vicinity of adipose tissue. Adipocytes together with the stromal vascular fractions (SVF) of the adipose tissue act to modulate the adhesion, migration and invasion of tumor cells.

The present study is designed to elucidate the role of adiponectin as a stromal factor in modulating the tumor microenvironment during breast cancer development in MMTV-PyVT mice. First, the presence of basal epithelial-like and metaplastic components is confirmed in the mammary tumors derived from adiponectin-deficient MMTV-PyVT mice. The metaplastic features originate mainly from SVF in adipose tissues of these mice. Second, the results demonstrated that in MMTV-PyVT mice lacking the expression of adiponectin, a subpopulation of CD44+CD25-CD100+ cells are enriched in SVF of adipose tissues. Co-implantation of these with human breast cancer MDA-MB-231 cells enhances the development of basal-like and metaplastic mammary tumors in NOD/SCID mice. Third, up-regulated CD100 expression suppresses Notch signaling in CD44+CD25- cells and inhibits the early T-cell development in the thymus. Fourth, adiponectin treatment down-regulates CD100 expression in the thymus and enhances Notch signaling in T-cells. Replenishment with adiponectin reduces the accumulation of CD44+CD25-CD100+ cells in mammary tumors of MMTV-PyVT mice.

Collectively, these results provide important evidence supporting the pivotal role of adiponectin in mediating epithelial-stroma cross-talks during mammary carcinogenesis.