Abstract
The development and functional cycle of the mammary gland involves a number of processes that are caricatured by breast cancer cells during invasion and metastasis. Expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 has been associated with metastatic, poor prognosis, and high-grade breast cancers. Since hypoxia affects normal epithelial differentiation, we hypothesise that HIFs are important for normal breast epithelial development and regeneration as well as cancer initiation and progression. Here, we investigated the expression of the oxygen-sensitive HIF-alpha subunits during mouse mammary gland development, lactation, and involution. In breast epithelial cells, HIF-1α was expressed during early development, prior to cell polarisation. In contrast, expression of HIF-2α occurred later and was restricted to a subpopulation of luminal epithelial cells in the lactating gland. Mammary gland involution is a developmental stage that involves extensive tissue remodelling with cell death but survival of tissue stem/progenitor cells. At this stage, HIF-2α, but little HIF-1α, was expressed in CK14-positive epithelial cells. The temporal but differential expression of the HIF-alpha subunits during the mammary gland life cycle indicates that their expression is controlled by additional factors to hypoxia. Further functional studies of the roles of these proteins in the mammary gland and breast cancer are warranted.
Highlights
In contrast to the development of most organs, mammary gland development takes place during embryogenesis and foetal life, and during three distinct phases: embryonal development, puberty, and pregnancy [1]
We recently showed that hypoxia and HIF transcriptional activity are linked to a state of loss of polarisation and a cancer-like phenotype in primary human breast epithelial cells [7,8]
We investigated the HIF staining pattern of the antibodies used in this study using tumours obtained from a transgenic mouse mammary tumour model (MMTV-PyMT) injected with Hypoxyprobe (Hypoxyprobe, USA) as reference tissue. Both HIF-1α and HIF-2α proteins were selectively detected in hypoxic peri-necrotic areas (Fig 1)
Summary
In contrast to the development of most organs, mammary gland development takes place during embryogenesis and foetal life, and during three distinct phases: embryonal development, puberty, and pregnancy [1]. The mammary epithelial anlage forms during embryogenesis and resides just beneath the nipple. The ductal tree forms by extensive epithelial proliferation and invasion of the mammary fat pad. Further branching of the ductal tree takes place during early pregnancy, when milk-producing alveoli are formed and, towards the end of pregnancy, final differentiation takes place and milk production is hormonally induced. The functional part of the mammary gland lifecycle, intensive metabolism is stimulated.
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