Interlobular and intralobular mammary stroma: Genotype may not reflect phenotype

Fleming, Jodie M.; Long, Ezhou L.; Ginsburg, Erika; Gerscovich, D; Meltzer, Paul S.; Vonderhaar, BK

doi:10.1186/1471-2121-9-46

Cited by 30 publications

(27 citation statements)

References 50 publications

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“…The growth and function of mammary epithelial cells relies on interactions with supportive stroma (85). The importance of epithelial‐stromal interactions has been shown in culture and in vivo (79, 86).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of epithelial‐stromal interactions has been shown in culture and in vivo (79, 86). Normally, epithelial cells are surrounded by stroma composed of mainly quiescent fibroblasts that secrete extracellular matrix components and provide a normal barrier to tumor formation (85, 86). Epithelial cell dysfunction has been shown to be an instigating factor in conversion of normal fibroblasts to cancer‐associated fibroblasts, which secrete significantly more collagen (87).…”

Section: Discussionmentioning

confidence: 99%

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CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment

Pierzchalski

Norman

et al. 2013

FASEB j.

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Cellular retinol-binding protein, type I (CrbpI), encoded by retinol-binding protein, type 1 (Rbp1), is a chaperone of vitamin A (retinol) that is epigenetically silenced in ~25% of human breast cancers. CrbpI delivers vitamin A to enzymes for metabolism into an active metabolite, all-trans retinoic acid (atRA), where atRA is essential to cell proliferation, apoptosis, differentiation, and migration. Here, we show the effect of CrbpI loss on mammary atRA homeostasis using the Rbp1(-/-) mouse model. Rbp1(-/-) mouse mammary tissue has disrupted retinoid homeostasis that results in 40% depleted endogenous atRA. CrbpI loss and atRA depletion precede defects in atRA biosynthesis enzyme expression. Compensation by CrbpIII as a retinoid chaperone does not functionally replace CrbpI. Mammary subcellular fractions isolated from Rbp1(-/-) mice have altered retinol dehydrogenase/reductase (Rdh) enzyme activity that results in 24-42% less atRA production. Rbp1(-/-) mammary tissue has epithelial hyperplasia, stromal hypercellularity, increased collagen, and increased oxidative stress characteristic of atRA deficiency and early tissue dysfunction that precedes tumor formation. Consistent with the findings from the Rbp1(-/-) mouse, tumorigenic epithelial cells lacking CrbpI expression produce 51% less atRA. Together, these data show that CrbpI loss disrupts atRA homeostasis in mammary tissue, resulting in microenvironmental defects similar to those observed at the early stages of tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment

Pierzchalski

Norman

et al. 2013

FASEB j.

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“…In addition to their obvious anatomical variations, there is a dramatic contrast in morphological features such as stromal composition (Fleming et al, 2008; Parmar and Cunha, 2004). In the mouse, the epithelium is embedded within a large amount of fat interspersed with a small amount of connective tissue.…”

Section: Introductionmentioning

confidence: 99%

“…In the mouse, the epithelium is embedded within a large amount of fat interspersed with a small amount of connective tissue. In contrast, human breast epithelium is more closely associated with the intra- and inter-lobular stroma, minimizing contact with adipose (Fleming et al, 2008). Therefore, injecting primary breast cancer cells directly into a more fatty mouse tissue presents a challenge for those cells to grow and retain their original pathological features.…”

Section: Introductionmentioning

confidence: 99%

Local regulation of human breast xenograft models

Fleming

Miller

Meyer

et al. 2010

Journal Cellular Physiology

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Breast cancer studies implant human cancer cells under the renal capsule, subcutaneously, or orthotopically and often use estrogen supplementation and immune suppressants (etoposide) in xenograft mouse models. However, cell behavior is significantly impacted by signals from the local microenvironment. Therefore, we investigated how the combinatorial effect of the location of injection and procedural differences affected xenograft characteristics. Patient-derived breast cancer cells were injected into mouse abdominal or thoracic mammary glands ± estrogen and/or etoposide pretreatment. Abdominal xenografts had increased tumor incidence and volume, and decreased latency (P<0.001) compared to thoracic tumors. No statistically significant difference in tumor volume was found in abdominal xenografts treated ± estrogen or etoposide; however, etoposide suppressed tumor volume in thoracic xenografts (P<0.02). The combination of estrogen and etoposide significantly decreased tumor incidence in both sites. In addition, mice treated ± estradiol were injected orthotopically or subcutaneously with well-characterized breast cancer cell lines (MCF7, ZR75-1, MDA MB-231, or MCF10Ca1h). Orthotopic injection increased tumor volume; growth varied with estrogen supplementation. Location also altered methylation status of several breast cancer-related gene promoters. Lastly, vascularization of orthotopic tumors was significantly enhanced compared to subcutaneous tumors. These data suggest that optimal xenograft success occurs with orthotopic abdominal injections and illustrate molecular details of the compelling influence of the local microenvironment on in vivo models.

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“…In contrast, the lobular units of the human breast are surrounded by loose intralobular connective tissue, consisting primarily of fibroblasts. This intralobular stroma is subsequently surrounded by a more compact interlobular stroma, which detaches the lobules and intralobular stroma from any substantial direct contact with the adipose tissue (Fleming, et al 2008). Thus, alterations in breast cellular communication in response to obesity in humans compared to mice may substantially vary, given the differences in amount and proximity of the adipose to the epithelium.…”

Section: Model Systemsmentioning

confidence: 99%

Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion?

Reaves¹,

Ginsburg²,

Bang³

et al. 2015

Endocrine-Related Cancer

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Dietary ingestion of persistent organic pollutants (POPs) correlates with developing obesity. Obesity alters metabolism, induces an inflammatory tissue microenvironment, and is also linked with diabetes and breast cancer risk/promotion of the disease. However, no direct evidence exists exploring the correlation among all three of these factors (POPs, obesity, and breast cancer). Herein, we present current correlative studies suggesting a causal link between POPs exposure through diet and their bioaccumulation in adipose that promotes the development of obesity and ultimately influences breast cancer development and/or progression. Furthermore, as endocrine disruptors, POPs can potentially interfere with hormonally responsive tissue functions causing dysregulation in hormone signaling and cell function. This review highlights the critical need for advanced in vitro and in vivo model systems to understand the complex relationship between obesity, POPs, breast cancer, and, more importantly, to delineate their multifaceted molecular, cellular, and biochemical mechanisms. Comprehensive in vitro and in vivo studies directly testing the observed correlations as well as detailing their molecular mechanisms are vital to cancer research and, ultimately, public health.

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Interlobular and intralobular mammary stroma: Genotype may not reflect phenotype

Cited by 30 publications

References 50 publications

CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment

CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment

Local regulation of human breast xenograft models

Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion?

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