Fibronectin and the α5β1 Integrin Are Under Developmental and Ovarian Steroid Regulation in the Normal Mouse Mammary Gland

Woodward, Terry L.; Mienaltowski, A. S.; Modi, Ronak; Bennett, Jessica M.; Haslam, Sandra Z.

doi:10.1210/endo.142.7.8273

Cited by 59 publications

(21 citation statements)

References 28 publications

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“…Fig. 1), correlating with increased Fn expression by pregnancy-associated hormonal conditions (Woodward et al, 2001) during alveologenesis (Williams et al, 2008). Together, our data indicate that Fn-deletion caused a significant decrease in the rate of mammary epithelial cell proliferation that accounted for the delay in ductal outgrowth in adult, virgin and impaired alveologenesis in pregnant Fn MEp−/− mice.…”

Section: Resultsmentioning

confidence: 83%

“…Among the three ECM proteins only the Fn levels changed appreciably, increasing threefold between puberty and sexual maturity and remaining high during pregnancy and lactation. This temporal expression of Fn coincided with increased expression of select growth factors and AP-1 transcription factors as well as estrogen and progesterone (Fendrick et al, 1998; Haslam and Woodward, 2003; Shen et al, 2006; Wang et al, 1994; Woodward et al, 1998; Woodward et al, 2001; Yang et al, 1995). Together these compounds are involved in ductal development during puberty and mammary epithelial cell proliferation, ductal branching and alveologenesis at sexual maturity and during pregnancy (Fendrick et al, 1998; Woodward et al, 1998), while AP-1 blockade suppresses ductal branching and budding and reduces gland tree size and fat pad occupancy in developing mammary glands by inhibiting expression of AP-1-dependent genes (e.g., Fn, cyclin D, c-myc, TIMP-1, vimentin) (Shen et al, 2006).…”

Section: Introductionmentioning

confidence: 96%

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Conditional knockout of fibronectin abrogates mouse mammary gland lobuloalveolar differentiation

Liu

Cheng

Flesken‐Nikitin

et al. 2010

Developmental Biology

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Fibronectin (Fn) plays an important part in the branching morphogenesis of salivary gland, lung, and kidney. Here, we examine the effect of the conditional knockout of Fn in the mammary epithelium [FnMEp−/−] on postnatal mammary gland development, using Cre-loxP mediated gene knockout technology. Our data show that Fn deletion causes a moderate retardation in outgrowth and branching of the ductal tree in 5-week old mice. These defects are partially compensated in virgin 16-week old mice. However, mammary glands consisting of Fn-deficient epithelial cells fail to undergo normal lobuloalveolar differentiation during pregnancy. The severity of lobuloalveolar impairment ranged from lobular hypoplasia to aplasia in some cases and was associated with the amount of Fn protein recovered from these glands. Decreased rates of mammary epithelial cell proliferation accounted for delayed ductal outgrowth in virgin and lack of alveologenesis in pregnant FnMEp−/− mice. Concomitant decreased expression of integrin β1 (Itgb1) and lack of autophosphorylation of focal adhesion kinase (Fak) suggest that this pathology might, at least in part, be mediated by disruption of the Fn/Itgb1/Fak signaling pathway.

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Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 96%

Conditional knockout of fibronectin abrogates mouse mammary gland lobuloalveolar differentiation

Liu

Cheng

Flesken‐Nikitin

et al. 2010

Developmental Biology

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“…We have also investigated the hormonal regulation and functional role of ECM proteins and integrins in vivo during mammary gland development [18]. Of Col I, LM and FN, only FN levels change appreciably, increasing threefold between puberty and sexual maturity and remaining high during pregnancy and lactation.…”

Section: Extracellular Matrix and Integrin-mediated Hormone Interactimentioning

confidence: 99%

Host microenvironment in breast cancer development: Epithelial-cell–stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland

2003

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208BrdU = bromodeoxyuridine; Col 1 = collagen type 1; ECM = extracellular matrix; EGF = epidermal growth factor; ER = estrogen receptor; FCM = fibroblast-conditioned medium; FN = fibronectin; HGF = hepatocyte growth factor; IGF-1 = insulin-like growth factor I; LM = laminin; PBS = phosphate-buffered saline; PR = progesterone receptor; R5020 = promegestone. Breast Cancer Research Vol 5 No 4 Haslam and Woodward IntroductionMammary gland growth and development are mediated through the complex interactions of steroid hormones, polypeptide hormones, growth stimulatory factors and growth inhibitory factors. Normal development and function of the mammary gland are also dependent upon complex interactions between epithelial cells and stromal cells [1,2]. Stromal cells can regulate the epithelium by the production of soluble growth stimulatory and/or inhibitory factors; and components of the extracellular matrix such as collagens, fibronectin and laminin can also act as signaling molecules for epithelial cells, via specific integrins on epithelial cells. Epithelial cells also secrete factors that influence proliferation and function of adjacent epithelial and stromal cells (Fig. 1).Although there have been numerous studies of signalling mediated by the extracellular matrix and integrin in normal mammary gland and breast cancer cell lines, none has addressed the role of stroma in mediating and modulating steroid hormone action. There is increasing evidence that a number of responses to estrogen and/or progesterone in the mammary gland may be mediated indirectly through paracrine effects. This review focuses on recent studies from our laboratory addressing interactions between epithelial cells and stromal cells and between steroid hormones and growth factors in the normal murine mammary gland and in human breast cancer cells. Steroid hormones and mammary gland developmentEstrogen and progesterone are required for proliferation and morphogenesis of the normal mammary gland. Estrogen drives ductal development during puberty, whereas estrogen + progesterone mediate the proliferative and morphological changes of ductal side-branching and alveologenesis that occur at sexual maturity and during pregnancy [1,2]. Progesterone is also mitogenic in the premenopausal and postmenopausal human breast [3]. The greater risk of breast cancer in postmenopausal women receiving combined estrogen plus progestin hormone replacement therapy than in those receiving AbstractMammary epithelial cells comprise the functional component of the normal gland and are the major target for carcinogenesis in mammary cancer. However, the stromal compartment of the normal gland and of tumors plays an important role in directing proliferative and functional changes in the epithelium. In vivo and in vitro studies of the murine mammary gland have provided insights into novel stromadependent mechanisms by which estrogen and progesterone action in the epithelium can be modulated by hepatocyte growth factor (HGF) and the extracellular matrix proteins, collagen typ...

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“…Namely, the addition of exogenous FN negatively impacts acinar differentiation in the mammary gland and creates a microenvironment conducive to the growth of mammary epithelia [5]. Integrin α5β1 and FN are prominently expressed in the mammary gland, and their basal expression is increased during active proliferation of mammary gland tissue in mice suggesting that this FN-integrin interaction may be required for hormone-dependent proliferation in the mammary gland [11]. In addition, transgenic mice expressing dominant-negative integrin β1 show disrupted mammary gland development that is associated in a loss of AKT activation and Shc-dependent extracellular regulated kinase-1 and -2 (Erk-1/-2) activation [12].…”

Section: Introductionmentioning

confidence: 99%

The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

et al. 2014

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The G protein-coupled estrogen receptor-1, GPER-1, coordinates fibronectin (FN) matrix assembly and release of heparan-bound epidermal growth factor (HB-EGF). This mechanism of action results in the recruitment of FN-engaged integrin α5β1 to fibrillar adhesions and the formation of integrin α5β1-Shc adaptor protein complexes. Here, we show that GPER-1 stimulation of murine 4 T1 or human SKBR3 breast cancer cells with 17β-estradiol (E2β) promotes the formation of focal adhesions and actin stress fibers and results in increased cellular adhesion and haptotaxis on FN, but not collagen. These actions are also induced by the xenoestrogen, bisphenol A, and the estrogen receptor (ER) antagonist, ICI 182, 780, but not the inactive stereoisomer, 17α-estradiol (E2α). In addition, we show that GPER-1 stimulation of breast cancer cells allows for FN-dependent, anchorage-independent growth and FN fibril formation in “hanging drop” assays, indicating that these GPER-1-mediated actions occur independently of adhesion to solid substrata. Stable expression of Shc mutant Y317F lacking its primary tyrosyl phosphorylation site disrupts E2β-induced focal adhesion and actin stress fiber formation and abolishes E2β-enhanced haptotaxis on FN and anchorage-dependent growth. Collectively, these data demonstrate that E2β action via GPER-1 enhances cellular adhesivity and FN matrix assembly and allows for anchorage-independent growth, cellular events that may allow for cellular survival, and tumor progression.

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Fibronectin and the α5β1 Integrin Are Under Developmental and Ovarian Steroid Regulation in the Normal Mouse Mammary Gland

Cited by 59 publications

References 28 publications

Conditional knockout of fibronectin abrogates mouse mammary gland lobuloalveolar differentiation

Conditional knockout of fibronectin abrogates mouse mammary gland lobuloalveolar differentiation

Host microenvironment in breast cancer development: Epithelial-cell–stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland

The G Protein-Coupled Estrogen Receptor-1, GPER-1, Promotes Fibrillogenesis via a Shc-Dependent Pathway Resulting in Anchorage-Independent Growth

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