IGF-IR Mediated Mammary Tumorigenesis Is Enhanced during Pubertal Development

Robert A Jones,Roger A Moorehead,Katrina L Watson,Craig I Campbell,Tatjana Adamovic

doi:10.1371/journal.pone.0108781

Robert A Jones, Roger A Moorehead + Show 3 more

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https://doi.org/10.1371/journal.pone.0108781

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Abstract

Although breast cancer typically develops in women over the age of 40, it remains unclear when breast cancer initiating events occur or whether the mammary gland is particularly susceptible to oncogenic transformation at a particular developmental stage. Using MTB-IGFIR transgenic mice that overexpress type I insulin-like growth factor receptor (IGF-IR) in a doxycycline-inducible manner, mammary tumorigenesis was initiated at different developmental stages. Tumor multiplicity was significantly increased while tumor latency was significantly decreased when the IGF-IR transgene was expressed during pubertal development compared to post-pubertal transgene expression. Moreover, metastatic spread of mammary tumors to the lungs was approximately twice as likely when IGF-IR was overexpressed in pubertal mice compared to post-pubertal mice. In addition, engraftment of pubertal MTB-IGFIR mammary tissue into cleared mammary fat pads of pubertal hosts produced tumors more frequently and faster than engraftment into adult hosts. These experiments show that the mammary microenvironment created during puberty renders mammary epithelial cells particularly susceptible to transformation.

Highlights

The mammary gland is a complex secretory organ that requires the interaction of multiple cell types for normal development and function
To investigate whether the developmental state of the mammary gland modulates mammary tumorigenesis, the IGF-IR transgene was induced during embryonic development, on postnatal day 21, on postnatal day 100 and after one complete cycle of pregnancy and lactation
Since pubertal mammary development begins at approximately 4–5 weeks of age in FVB mice and is completed by approximately 8–10 weeks of age, expressing the IGF-IR transgene at postnatal day 21 ensures that the transgene is elevated during pubertal development while expressing the IGF-IR transgene at postnatal day 100 ensures that pubertal mammary development has been completed prior to IGF-IR overexpression

Summary

Introduction

The mammary gland is a complex secretory organ that requires the interaction of multiple cell types for normal development and function. A diverse array of stromal cells including adipocytes, vascular endothelial, fibroblasts and immune cells constitute the mammary fat pad in which the ductal epithelial network is embedded [1,2,3]. Mammary gland development can be divided into distinct stages that begin during embryogenesis and continue throughout reproductive maturity and adulthood. Multipotent fetal mammary stem cells give rise to a rudimentary bilayared ductal tree that remains quiescent until the onset of puberty. Following cessation of milk production, involution leads to the collapse of lobuloalveoli and returns the mammary gland to the pre-pregnant state. The virgin adult mammary gland is often considered as ‘resting’

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