Leptin Receptor-Deficient MMTV-TGF-α/Lepr<sup>db</sup> Lepr<sup>db</sup> Female Mice Do Not Develop Oncogene-Induced Mammary Tumors

Cleary, Margot P.; Juneja, Subhash C.; Phillips, F. C.; Hu, Xin; Grande, Joseph P.; Maihle, Nita J.

doi:10.1177/153537020422900207

Cited by 141 publications

(99 citation statements)

References 67 publications

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“…Leptin has been implicated as a growth-promoting factor for Brca [1]. Animal studies also support a role for leptin in mammary tumor development as evidenced by the fact that mice deficient in leptin, Lep ob Lep ob [4], or with non-functioning leptin receptors, Lepr db Lepr db [5], did not develop transgene-induced mammary tumors. It is possible that the levels of adiponectin and leptin receptors, as well as the balance of serum adiponectin and leptin, are critical factors in mammary tumorigenesis.…”

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confidence: 69%

Balance of adiponectin and leptin modulates breast cancer cell growth

et al. 2008

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There is lack of information concerning how the ratio of adiponectin to leptin in serum affects breast cancer (Brca) proliferation. It is possible that the link between obesity and increased risk for aggressive Brca is in part due to the milieu of cytokines synthesized and released by the adipose tissue [1]. Adiponectin (also known as adipocyte complement-related protein of 30 kDa (Acrp30)) and leptin are two specific cytokines secreted by the adipose tissue. Acrp30 serum levels decrease with increasing fatness while leptin levels increase. Functionally, they appear to oppose each other's actions. Acrp30 can block proliferation of Brca cells [2]. In vitro assays have shown that a number of different Brca cell lines express one or both of the Acrp30 receptors and show reduced growth and/or increased apoptosis in response to Acrp30 [3]. Leptin has been implicated as a growth-promoting factor for Brca [1]. Animal studies also support a role for leptin in mammary tumor development as evidenced by the fact that mice deficient in leptin, Lep ob Lep ob [4], or with non-functioning leptin receptors, Lepr db Lepr db [5], did not develop transgene-induced mammary tumors. It is possible that the levels of adiponectin and leptin receptors, as well as the balance of serum adiponectin and leptin, are critical factors in mammary tumorigenesis.We investigated the effects of Acrp30 and a naturally truncated form known as globular Acrp30 [6] (gAcrp30) in the presence or absence of leptin. There are two different Acrp30 receptors, designated as AdipoR1 and AdipoR2 [7]. Full-length Acrp30 binds with highest affinity to AdipoR2, and gAcrp30 binds with highest affinity to AdipoR1 [7]. The serum levels of gAcrp30 in women with Brca have not yet been fully investigated, nor has the role of gAcrp30 in Brca development. We performed proliferation assays with the MDA-MB-231 (MDA-wt) ERα negative Brca cell line and the MDA-ERα7 cell line which we developed by stably integrating the ERα gene such that it now exhibits increased growth in vivo in the presence of exogenous estradiol [8]. Leptin is present in the serum of almost all humans in the range of 5-50 ng/ ml [9]. However, in obese individuals levels in excess of 100 ng/ml are common. The addition of leptin (50 ng/ml) to these two cell lines caused a slight increase in proliferation ( Figure 1A) for both the MDA-wt and MDA-ERα7 cells after 48 h. Acrp30 is measured in human serum in the range of 2-20 μg/ml and is negatively correlated with body weight, BMI, body fat and serum leptin in women [10]. When these two cell lines were treated with Acrp30 and gAcrp30 there was a reduction in proliferation of the MDA-wt and MDA-ERα7 cells as compared to leptintreated cells. To investigate how changes in the ratio of leptin and Acrp30 or gAcrp30 affect cell growth, we performed proliferation assays using ratios of Acrp30 to leptin that simulate the physiological balance found with increasing body weight, i.e., by decreasing adiponectin and increasing leptin. A high ratio of Acrp30 to leptin caused...

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confidence: 69%

Balance of adiponectin and leptin modulates breast cancer cell growth

et al. 2008

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“…[46][47][48] Furthermore, we have reported that genetically obese leptin-(Lep) and leptin High fat diet and MT latency MP Cleary et al receptor-(Lepr) deficient mice crossbred with MMTV-TGF-a mice did not develop MTs. 24,25 Although we did not determine serum leptin levels in the present study, it has been reported that serum leptin levels were highest in obesity-prone rats compared to obesity-resistant and control rats, while obesity-resistant rats had higher leptin levels than the control rats. 49 In a second study, comparing only high fat fed animals, obesity-prone rats had higher plasma leptin than did obesity-resistant rats.…”

Section: Discussionmentioning

confidence: 93%

“…23 When followed to 24 months of age MT incidence was increased to at least 50%. 24,25 Here we describe the effect on body weight and MT development while feeding normally lean MMTV-TGF-a female mice a moderately high fat diet from 10 until 85 weeks of age.…”

Section: Introductionmentioning

confidence: 99%

Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-α mice

2004

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OBJECTIVE:The role of high fat diets in breast cancer/mammary tumor (MT) development is controversial. This may be partially attributable to variable effects of high fat diets on body weight. Here, we used a moderately high fat diet (32.5% fat calories) expected to cause obesity in most mice, but predicted to result in some mice remaining in the weight range of mice fed the low fat diet (11% fat calories). This provided the opportunity to compare mice fed the high fat diet exhibiting different body weights and mice of similar weight consuming high vs low fat diets. EXPERIMENTAL METHODS: Transgenic MMTV-TGF-a mice, a model of postmenopausal breast cancer, consumed a low fat diet, that is, chow-fed (n ¼ 25) or a moderately high fat diet from 10 weeks of age (n ¼ 51). Body weight at 34 weeks of age was used to assign high fat diet mice to obesity-prone4overweight4obesity-resistant groups (n ¼ 17) (Po0.0001). Mice were euthanized when MTs developed or at 85 weeks of age. RESULTS: Final body weights were highest in obesity-prone4overweight 4obesity-resistant ¼ chow-fed mice. Fat pads and fat pad:carcass were heaviest in obesity-prone followed by overweight mice. However, obesity-resistant mice had fat pad weights and fat pad:carcass three-fold greater than chow-fed mice. All groups had MT incidences between 72 and 82%. Obesity-prone mice exhibited the shortest MT latency (Po0.0001), but obesity-resistant mice had significantly shorter latency than chow-fed mice. CONCLUSIONS: Consumption of a high fat diet increased adiposity and shortened MT latency in relation to its effect on body weight. These results indicate a complex role of dietary fat level on mammary tumorigenesis.

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“…Moreover, addition of leptin to MCF-7 breast cancer cells decreases the expression of the cancer suppression protein p53, exploiting cancer cell survival property [40]. In a female transgenic mouse model susceptible to mammary tumor growth, deficiency of either the leptin gene (ob/ob) [41] or its receptor (db/db) resulted in no development of mammary tumors, whereas tumors were detected in over half of the controls [42].…”

Section: Leptinmentioning

confidence: 99%

Adipose tissue, obesity and adipokines: role in cancer promotion

Booth

Magnuson

Fouts

et al. 2015

Hormone Molecular Biology and Clinical Investigation

250

235

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Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term "adiposopathy" is used to describe this promotion of pathogenic adipocytes and associated adipose -elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of wellcharacterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.

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Leptin Receptor-Deficient MMTV-TGF-α/Lepr^db Lepr^db Female Mice Do Not Develop Oncogene-Induced Mammary Tumors

Cited by 141 publications

References 67 publications

Balance of adiponectin and leptin modulates breast cancer cell growth

Balance of adiponectin and leptin modulates breast cancer cell growth

Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-α mice

Adipose tissue, obesity and adipokines: role in cancer promotion

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Leptin Receptor-Deficient MMTV-TGF-α/Leprdb Leprdb Female Mice Do Not Develop Oncogene-Induced Mammary Tumors

Cited by 141 publications

References 67 publications

Balance of adiponectin and leptin modulates breast cancer cell growth

Balance of adiponectin and leptin modulates breast cancer cell growth

Effect of high fat diet on body weight and mammary tumor latency in MMTV-TGF-α mice

Adipose tissue, obesity and adipokines: role in cancer promotion

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Leptin Receptor-Deficient MMTV-TGF-α/Lepr^db Lepr^db Female Mice Do Not Develop Oncogene-Induced Mammary Tumors