P190-B Rho GTPase-Activating Protein Overexpression Disrupts Ductal Morphogenesis and Induces Hyperplastic Lesions in the Developing Mammary Gland

Vargo-Gogola, Tracy; Heckman, Brandy M.; Gunther, Edward J.; Chodosh, Lewis A.; Rosen, Jeffrey M.

doi:10.1210/me.2005-0426

Cited by 48 publications

(67 citation statements)

References 31 publications

(35 reference statements)

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“…Interestingly, increased level of p190-B was found in a subset of mutageninduced mammary tumors (36) and inducible expression of p190-B in mammary gland during pregnancy results in hyperplastic lesions (37). Although these findings suggest a potential role of deregulated p190-B in mammary malignancy, p190-B is probably not a substrate of Brk, as the sequences flanking the residue equivalent to Y 1105 in p190-B are not conserved.…”

Section: Discussionmentioning

confidence: 99%

Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion

et al. 2008

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Breast tumor kinase (Brk), an Src-like nonreceptor tyrosine kinase, is overexpressed in breast cancer and several other cancer types. Our previous study indicates that Brk promotes cell migration and tumor invasion by phosphorylating the focal adhesion protein paxillin. Here, we report the identification of p190RhoGAP-A (p190) as a Brk substrate. Brk phosphorylates p190 at the Y 1105 residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively. In carcinoma cells expressing high levels of Brk, endogenous Brk functions as a key contributor to epidermal growth factor-induced p190 tyrosine phosphorylation. We present evidence showing that p190 phosphorylation plays essential roles in both migratory and proliferative effects of Brk. Furthermore, disruption of p190 phosphorylation-induced p190/p120 complex in breast cancer cells abolishes not only the abilities of Brk to regulate RhoA and Ras but also the stimulatory effects of Brk on proliferation, migration, invasion, transformation, and tumorigenicity. Together, our findings reveal a previously unknown function of Brk in regulating both RhoA and Ras by phosphorylating p190 and provide evidence for the crucial roles of this Brk-elicited signaling pathway in promoting breast malignancy.

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Section: Discussionmentioning

confidence: 99%

Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion

et al. 2008

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“…32,55 In conclusion, we demonstrate that overexpression of CrkII is associated with altered mammary gland development and accelerated tumor development. Based on the results obtained from the MMTV/CrkII transgenic mice and the microarray profile obtained from the T47D-CrkII cells, overexpression of CrkII alters mammary gland development in a multifactorial manner.…”

mentioning

confidence: 56%

“…19 This retarded phenotype is similar to other mouse models, such as MMTV/heregulin, MMTV/ EphB4, MMTV/Cripto, and mice overexpressing either Krct or p190-B Rho GTPase. 26,[32][33][34][35] For MMTV/CrkII mice, delayed outgrowth is associated with increased collagen surrounding the terminal end buds, with no significant changes in cellular proliferation, apoptosis, cellϪcell contact, differentiation, or macrophage recruitment despite the increased diameter of the terminal end buds themselves (Supplemental Figure S1 and S2 at http://ajp.amjpathol.org).…”

Section: Discussionmentioning

confidence: 99%

CrkII Transgene Induces Atypical Mammary Gland Development and Tumorigenesis

Fathers

Rodrigues

Zuo

et al. 2010

The American Journal of Pathology

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The v-Crk protein was originally isolated as the oncogene fusion product of the CT10 chicken retrovirus. Cellular homologues of v-Crk include Crk , which encodes two alternatively spliced proteins (CrkI and CrkII) , and CrkL. Though CrkI/II proteins are elevated in several types of cancer , including breast, the question of whether these Crk adaptor proteins can promote breast cancer has not been addressed. We created a transgenic mouse model that allows the expression of CrkII through the hormonally responsive mouse mammary tumor virus promoter. During puberty , transgenic mice were found to have delayed ductal outgrowth , characterized by increased collagen surrounding the terminal end buds. In post-pubertal mice , precocious ductal branching was observed and associated with increased proliferation. Crk was originally isolated as the oncogene fusion product of the CT10 chicken retrovirus (v-Crk) in chicken fibrosarcomas.1 Cellular homologues of v-Crk include cCrk, which encodes two proteins (c-CrkI and c-CrkII) through alternative splicing, and the related protein cCrkL. Crk proteins consist of Src homology 2 (SH2) and Src homology 3 (SH3) domains.2 CrkI contains one SH2 domain and one SH3 domain, whereas CrkII also contains a linker region (containing a Y221 negative regulatory site) and a second SH3 domain at the C-terminus.

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“…However, these data also show that P-cadherin plays a more lineage-restricted role in MEP self-organizing. osin regulatory network in normal morphogenesis (15,16). We therefore examined the impact on HMEC self-organization of the actomyosin network inhibitors ML-7, a myosin light-chain kinase (MLCK) inhibitor (17), and Y27632, a Rho kinase (ROCK) inhibitor that blocks both ROCK1 and ROCK2 (18).…”

Section: Functional Identification Of Adhesion Molecules That Drive Tmentioning

confidence: 99%

Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells

Chanson

Brownfield

Garbe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Loss of organization is a principle feature of cancers; therefore it is important to understand how normal adult multilineage tissues, such as bilayered secretory epithelia, establish and maintain their architectures. The self-organization process that drives heterogeneous mixtures of cells to form organized tissues is well studied in embryology and with mammalian cell lines that were abnormal or engineered. Here we used a micropatterning approach that confined cells to a cylindrical geometry combined with an algorithm to quantify changes of cellular distribution over time to measure the ability of different cell types to self-organize relative to each other. Using normal human mammary epithelial cells enriched into pools of the two principal lineages, luminal and myoepithelial cells, we demonstrated that bilayered organization in mammary epithelium was driven mainly by lineage-specific differential E-cadherin expression, but that P-cadherin contributed specifically to organization of the myoepithelial layer. Disruption of the actomyosin network or of adherens junction proteins resulted in either prevention of bilayer formation or loss of preformed bilayers, consistent with continual sampling of the local microenvironment by cadherins. Together these data show that self-organization is an innate and reversible property of communities of normal adult human mammary epithelial cells. mammary gland | tissue biology M ost mammalian adult tissues are replenished and repaired throughout life by reservoirs of stem cells. As new somatic cells replace old ones or build new tissue, organization and architecture must be maintained. The alternative, loss of organization in adult tissues, is associated with cancer and other diseases. Lineage-specific progenitors or their differentiated progeny must have a means to reach their ultimate site of residence within the adult tissue. The robust ability to organize cells into tissues is marked from conception: Heterogeneous aggregates of dissociated cells from embryonic tissues, suspended in gels or hanging droplets or on agarose-coated plates, self-organize into semblances of the original tissues (1-5). The mechanisms governing self-organization during developmental morphogenesis (6-10) are likely conserved in the maintenance of organization in adult tissues. Here we use normal human mammary epithelial cells (HMEC) as a model to determine how organized states are preserved in normal adult epithelia.The mammary gland undergoes cycles of proliferation and involution, showing as much as a 10-fold expansion in preparation for lactation followed by return to normal size. During these processes, the precise bilayered branching organization throughout the gland is maintained; secretory luminal epithelial cells (LEPs) line the lumen, surrounded by a layer of contractile myoepithelial cells (MEPs) that are adjacent to the basement membrane. We hypothesized that mammary epithelial cells possessed lineage-specific intrinsic abilities to self-organize into domains of lineage specificity. Such a...

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P190-B Rho GTPase-Activating Protein Overexpression Disrupts Ductal Morphogenesis and Induces Hyperplastic Lesions in the Developing Mammary Gland

Cited by 48 publications

References 31 publications

Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion

Breast Tumor Kinase Phosphorylates p190RhoGAP to Regulate Rho and Ras and Promote Breast Carcinoma Growth, Migration, and Invasion

CrkII Transgene Induces Atypical Mammary Gland Development and Tumorigenesis

Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells

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