Genetic Mechanisms in Apc-Mediated Mammary Tumorigenesis

Mari Kuraguchi,Raju Kucherlapati,Nana Yaw Ohene-Baah,Roderick Terry Bronson,Dmitriy Sonkin,Eva Y.-H P Lee

doi:10.1371/journal.pgen.1000367

Abstract

Many components of Wnt/β-catenin signaling pathway also play critical roles in mammary tumor development, yet the role of the tumor suppressor gene APC (adenomatous polyposis coli) in breast oncongenesis is unclear. To better understand the role of Apc in mammary tumorigenesis, we introduced conditional Apc mutations specifically into two different mammary epithelial populations using K14-cre and WAP-cre transgenic mice that express Cre-recombinase in mammary progenitor cells and lactating luminal cells, respectively. Only the K14-cre–mediated Apc heterozygosity developed mammary adenocarcinomas demonstrating histological heterogeneity, suggesting the multilineage progenitor cell origin of these tumors. These tumors harbored truncation mutation in a defined region in the remaining wild-type allele of Apc that would retain some down-regulating activity of β-catenin signaling. Activating mutations at codons 12 and 61 of either H-Ras or K-Ras were also found in a subset of these tumors. Expression profiles of acinar-type mammary tumors from K14-cre; ApcCKO/+ mice showed luminal epithelial gene expression pattern, and clustering analysis demonstrated more correlation to MMTV-neu model than to MMTV-Wnt1. In contrast, neither WAP-cre–induced Apc heterozygous nor homozygous mutations resulted in predisposition to mammary tumorigenesis, although WAP-cre–mediated Apc deficiency resulted in severe squamous metaplasia of mammary glands. Collectively, our results suggest that not only the epithelial origin but also a certain Apc mutations are selected to achieve a specific level of β-catenin signaling optimal for mammary tumor development and explain partially the colon- but not mammary-specific tumor development in patients that carry germline mutations in APC.

Highlights

Breast cancer is one of the most common malignancies in women in Western countries and it is the cause of death in approximately 20% of all females who die from cancer
To study the role of Apc in mammary tumorigenesis, we introduced conditional Apc mutations into two different mammary epithelial populations using K14 (Keratin 14)-cre and whey acid protein (WAP) (Whey Acidic Protein)-cre transgenic mice that express Cre recombinase in mammary progenitor cells and lactating luminal cells, respectively
We show that a specific type of Apc somatic mutations in mammary progenitor/stem cell population in mice induces mammary carcinomas with histological and molecular heterogeneity, but a complete deletion leads to squamous metaplasia

Summary

Introduction

Breast cancer is one of the most common malignancies in women in Western countries and it is the cause of death in approximately 20% of all females who die from cancer. Breast epithelium is a dynamic organ capable of rapid proliferation and functional differentiation upon pregnancy and lactation, followed by involution and remodeling at the end of each lactation period. In the ducts and alveoli, the mammary epithelium is organized into two layers, a basal layer of myoepithelial cells and a luminal epithelial layer. The myoepithelial cells, like other basal epithelial cells, express basal keratins (in particular, K5 and K14), P-cadherin, and the transcription factor p63 [1]. They contain smooth muscle-specific proteins, including the a-smooth muscle actin (aSMA), which confer contractility. Luminal cells express K8 and K18, which are characteristics of simple epithelia and when fully differentiated, secrete milk proteins [1]

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