Pattern of expression of the KGF receptor and its ligands KGF and FGF-10 during postnatal mouse mammary gland development

Abstract

The expression of the KGF receptor (KGFR) and its stromal ligands, KGF and FGF‐10, was compared during mouse mammary gland development. KGFR expression in mammary parenchyma is maximal in mature virgin mice, declines during pregnancy and lactation, but rises after weaning. The rise in KGFR mRNA in the virgin animal corresponds to parenchymal growth. The fall in KGFR expression in pregnancy is driven by hormone‐induced alveolar differentiation since the level of KGFR mRNA is 5‐fold higher in isolated ductal cells compared to alveolar cells. KGF and FGF‐10 expression patterns differ during ductal development. FGF‐10 is also expressed at about a 15‐fold higher molar level than KGF. During pregnancy and lactation, expression of KGF and FGF‐10 decreases in intact fat pads but is unchanged in parenchyma‐free fat pads. Thus, the decrease in KGF and FGF‐10 expression observed in intact glands during pregnancy and lactation is not a direct consequence of the changing hormonal milieu but more likely reflects an increase in the ratio of epithelium to stroma. Differences in the level and pattern of expression of mRNA for KGF, FGF‐10, and the KGFR during postnatal development of the mouse mammary gland are a result of morphological development, changes in the ratio of stroma to epithelium, and hormonal regulation of cell differentiation. These changes suggest that the biological roles that these growth factors play are regulated by fluctuations in both growth factor and growth factor receptor expression and that KGF and FGF‐10 may have different regulatory functions. Mol. Reprod. Dev. 56:441–447, 2000. © 2000 Wiley‐Liss, Inc.

Attenuation and loss of hormonal modulation of KGF (FGF-7)/KGF receptor expression and mitogenesis during mammary tumor progression

“…There is some evidence that KGF expression may be induced by estrogen in stromal cells. 17␤-estradiol has been reported to elevate KGF expression in stroma from breast cancer but not normal breast (Zhang et al, 1998), whereas we find that in vivo estrogen treatment can raise the level of stromal KGF expression in normal mouse mammary glands (Pedchenko and Imagawa, 2000). In cultured endometrial stroma, long-term DES exposure resulted in an elevation of KGF expression (Li and Rinehart, 1998).…”

In vivo inhibition of keratinocyte growth factor receptor expression by estrogen and antagonism by progesterone in the mouse mammary gland

“…It is clear that the synthesis of the KGFR is dependent upon the ratio of estradiol and progesterone. Variation in the level of KGFR mRNA during different stages of mammary gland development could reflect this (Pedchenko & Imagawa 2000b). KGFR expression is highest at 2-3 weeks of age and decreases through the peripubertal period when animals begin cycling.…”

“…It rises again in mature animals when progesterone exposure increases. KGFR expression in extracts of total mammary gland RNA is low during pregnancy which likely reflects lower expression in alveolar cells that is independent of the hormonal milieu of pregnancy (Pedchenko & Imagawa 2000b) and consistent with a vastly reduced mitogenic response of alveolar cells to KGF in vitro (W Imagawa & V K Pedchenko, unpublished observations). We can speculate that when estradiol and progesterone are both elevated (as during pregnancy), the level of KGFR in ductal epithelium is maintained while KGF synthesis is stimulated.…”

“…There is evidence that estradiol stimulation of ductal growth is mediated by an increase in epithelial epidermal growth factor (EGF) receptors and EGF levels , Ankrapp et al 1998. Other evidence shows that the expression of growth factors can change during different stages of mammary gland development raising the possibility of hormonal regulation (Pedchenko & Imagawa 2000b). We have begun to delineate the interactions of hormones with growth factors in the mammary gland by examining the hormonal regulation of the synthesis of keratinocyte growth factor (KGF or FGF-7) and its receptor, the KGF receptor .…”

“…We have begun to delineate the interactions of hormones with growth factors in the mammary gland by examining the hormonal regulation of the synthesis of keratinocyte growth factor (KGF or FGF-7) and its receptor, the KGF receptor . KGF is a stromal growth factor that is expressed in intact or parenchymafree mammary glands while the receptor is expressed only in mammary epithelium (Finch et al 1995, Pedchenko & Imagawa 2000b). Progesterone and prolactin are mammogenic hormones that are directly mitogenic towards mouse mammary epithelial cells in primary culture (Imagawa et al 1985) and can synergize with KGF in stimulating proliferation (Pedchenko & Imagawa 1998).…”