CD44 Promotes Epithelial Mammary Gland Development and Exhibits Altered Localization during Cancer Progression

Louderbough, Jeanne M.; Brown, Jessie; Nagle, Ray B.; Schroeder, Joyce A.

doi:10.1177/1947601911428223

Cited by 25 publications

(18 citation statements)

References 33 publications

(38 reference statements)

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“…Proper organization of myoepithelial and luminal epithelial cells is crucial for the normal structure and function of mammary glands [35]. Moreover, the myoepithelial layer is not only abundant in stem cells but also associated with cell differentiation during mammary gland development [36], [37], [38] and to suppress tumor development [39], [40].…”

Section: Resultsmentioning

confidence: 99%

“…Bocker and his colleagues described a population of normal human breast cells that express cytokeratin-5/6 (CK5/6) and represent stem cells that give rise to both differentiated luminal cells and myoepithelial cells [43]. The adhesion receptor CD44, which is also a stem cell marker, is expressed in the myoepithelium of the developing mammary gland, mediates epithelial-stromal and cell-cell interactions and modulates ductal development [35]. In another study, three distinct human breast epithelial subsets (basal and myoepithelial cells; luminal progenitor cells, and luminal cells) were identified from the resultant lineage-negative (Lin-) population with antibodies against CD49f and epithelial cell adhesion molecule (EpCAM).…”

Section: Discussionmentioning

confidence: 99%

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Atbf1 Regulates Pubertal Mammary Gland Development Likely by Inhibiting the Pro-Proliferative Function of Estrogen-ER Signaling

et al. 2012

PLoS ONE

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ATBF1 is a candidate tumor suppressor that interacts with estrogen receptor (ER) to inhibit the function of estrogen-ER signaling in gene regulation and cell proliferation control in human breast cancer cells. We therefore tested whether Atbf1 and its interaction with ER modulate the development of pubertal mammary gland, where estrogen is the predominant steroid hormone. In an in vitro model of cell differentiation, i.e., MCF10A cells cultured in Matrigel, ATBF1 expression was significantly increased, and knockdown of ATBF1 inhibited acinus formation. During mouse mammary gland development, Atbf1 was expressed at varying levels at different stages, with higher levels during puberty, lower during pregnancy, and the highest during lactation. Knockout of Atbf1 at the onset of puberty enhanced ductal elongation and bifurcation and promoted cell proliferation in both ducts and terminal end buds of pubertal mammary glands. Enhanced cell proliferation primarily occurred in ER-positive cells and was accompanied by increased expression of ER target genes. Furthermore, inactivation of Atbf1 reduced the expression of basal cell markers (CK5, CK14 and CD44) but not luminal cell markers. These findings indicate that Atbf1 plays a role in the development of pubertal mammary gland likely by modulating the function of estrogen-ER signaling in luminal cells and by modulating gene expression in basal cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Atbf1 Regulates Pubertal Mammary Gland Development Likely by Inhibiting the Pro-Proliferative Function of Estrogen-ER Signaling

et al. 2012

PLoS ONE

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“…Moreover, Pdpn can interact with CD44 (Martin-Villar et al, 2010). As mammary basal cells express CD44 (Louderbough et al, 2011), a molecular cooperation with Pdpn is possible.…”

Section: Pdpn Interferes With the Wnt/β-cat Signaling Cascade In Mammmentioning

confidence: 99%

Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling

et al. 2018

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Stem cells (SCs) drive mammary development, giving rise postnatally to an epithelial bilayer composed of luminal and basal myoepithelial cells. Dysregulation of SCs is thought to be at the origin of certain breast cancers; however, the molecular identity of SCs and the factors regulating their function remain poorly defined. We identified the transmembrane protein podoplanin (Pdpn) as a specific marker of the basal compartment, including multipotent SCs, and found Pdpn localized at the basal-luminal interface. Embryonic deletion of targeted to basal cells diminished basal and luminal SC activity and affected the expression of several Wnt/β-catenin signaling components in basal cells. Moreover, Pdpn loss attenuated mammary tumor formation in a mouse model of β-catenin-induced breast cancer, limiting tumor-initiating cell expansion and promoting molecular features associated with mesenchymal-to-epithelial cell transition. In line with the loss-of-function data, we demonstrated that mechanistically Pdpn enhances Wnt/β-catenin signaling in mammary basal cells. Overall, this study uncovers a role for Pdpn in mammary SC function and, importantly, identifies Pdpn as a new regulator of Wnt/β-catenin signaling, a key pathway in mammary development and tumorigenesis.

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“…Metastasis is a highly competitive process, whereby of the abundance of tumour cells that enter the blood circulation, only the fittest cells can survive . The metastatic cascade consists of three critical steps: (i) attachment of tumour cells to the ECM via cell surface receptors (ii) degradation of the matrix components by proteolytic enzymes; and (iii) migration through the degraded components (Fig. ).…”

Section: Basic Mechanism Of Tumour Invasion and Metastasismentioning

confidence: 99%

Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects

Wong

Sidik

Mahmud

et al. 2013

Clin Exp Pharma Physio

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Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.

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CD44 Promotes Epithelial Mammary Gland Development and Exhibits Altered Localization during Cancer Progression

Cited by 25 publications

References 33 publications

Atbf1 Regulates Pubertal Mammary Gland Development Likely by Inhibiting the Pro-Proliferative Function of Estrogen-ER Signaling

Atbf1 Regulates Pubertal Mammary Gland Development Likely by Inhibiting the Pro-Proliferative Function of Estrogen-ER Signaling

Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling

Molecular targets in the discovery and development of novel antimetastatic agents: Current progress and future prospects

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