Valerie B Holcomb's research while affiliated with Concordia University Texas and other places

Publications (24)

Article
Luminal breast tumors with little or no estrogen receptor-α expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the insulin-like growth factor 1 (IGF1)-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal...
Article
Background: Evidence shows that obesity increases the risk and mortality of many cancers, specifically breast cancer in post-menopausal women. Epidemiological studies demonstrate that males are at an increased risk for developing obesity, diabetes, and cancer compared to females, and after menopause, females mimic the males in their susceptibility...
Article
Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. Ovariectomized female mice were fed diets t...
Article
Obesity increases the risk of diabetes. The dysregulation of estrogen metabolism has been associated with the susceptibility to obesity and diabetes. Here, we explore the role estrogen plays in sex differences in obesity and glucose metabolism, specifically adipocyte biology. We randomized C57BL/6 J male, non-ovariectomized female, ovariectomized f...
Article
Background: Alcohol consumption is an established risk factor for breast cancer. Yet, the mechanism by which alcohol affects breast cancer development remains unresolved. The transition from the premenopausal to the postmenopausal phase is associated with a drastic reduction in systemic estrogen levels. It is not clear whether the risk of breast c...
Article
The risk of developing breast cancer and fatty liver is increased by alcohol consumption. The objective of the present study was to determine if obesity and exogenous estrogen supplementation alter the effects of alcohol on mammary tumorigenesis and fatty liver. Ovariectomized female mice were (1) fed diets to induce overweight and obese phenotypes...
Article
Obesity is associated with insulin resistance, liver steatosis and low-grade inflammation. The role of oestrogen in sex differences in the above co-morbidities is not fully understood. Our aim was to assess the role oestrogen has in modulating adipocyte size, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. To...
Article
Alcohol, obesity and estrogen modulate mammary tumor growth through adiposity and angiogenensis Jina Hong, Valerie B. Holcomb, and Nomelí P Núñez Background: Alcohol consumption increases breast cancer risk in women. Postmenopausal women who consume alcohol come in all shapes and sizes, including overweight and obese; some of these women may also t...
Article
Full-text available
Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. T...
Article
Epidemiological data show that in women, alcohol has a beneficial effect by increasing insulin sensitivity but also a deleterious effect by increasing breast cancer risk. These effects have not been shown concurrently in an animal model of breast cancer. Our objective is to identify a mouse model of breast cancer whereby alcohol increases insulin s...
Article
Alcohol consumption increases breast cancer risk in postmenopausal women in a dose-dependent manner. The objective of the present study was to determine if the effect of alcohol on mammary cancer is modified by body weight and exogenous estrogen. Ovariectomized mice of various body weights, receiving estrogen or placebo supplementation, and consumi...
Article
Full-text available
Ku80 is often referred to as a tumor suppressor since it maintains the genome by repairing DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. Even though Ku80 deletion causes hypersensitivity to gamma-radiation, DNA damage and chromosomal rearrangements, Ku80-mutant mice exhibit very low cancer levels. We previously h...
Article
Obesity is increasing worldwide. Estrogen protects female mice from gaining weight in contrast to ovariectomy. Excess weight can inhibit wound healing. We determine the effects of obesity on wound healing in the presence and absence of estrogen. For this purpose, we generated (ovariectomized (OVX) and non-ovariectomized (NOVX)) lean mice by feeding...
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Full-text available
Ku80 facilitates DNA repair and therefore should suppress cancer. However, ku80(-/-) mice exhibit reduced cancer, although they age prematurely and have a shortened life span. We tested the hypothesis that Ku80 deletion suppresses cancer by enhancing cellular tumor-suppressive responses to inefficiently repaired DNA damage. In support of this hypot...
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[This corrects the article on p. e192 in vol. 2, PMID: 17173483.].
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Full-text available
Ku70 forms a heterodimer with Ku80, called Ku, that is critical for repairing DNA double-stand breaks by nonhomologous end joining and for maintaining telomeres. Mice with either gene mutated exhibit similar phenotypes that include increased sensitivity to ionizing radiation and severe combined immunodeficiency. However, there are also differences...
Article
Animal models of premature aging are often defective for DNA repair. Ku80-mutant mice are disabled for nonhomologous end joining; a pathway that repairs both spontaneous DNA double-strand breaks (DSBs) and induced DNA DSBs generated by the action of a complex composed of Rag-1 and Rag-2 (Rag). Rag is essential for inducing DSBs important for assemb...
Article
The HPRT minigene is a selection cassette used for gene targeting in mouse embryonic stem (ES) cells and, it is unique since selection may be applied for its presence and absence. This minigene has two exon clusters separated by a small intron and splicing sequences. We find these exon clusters splice into exons from the target gene forming two dif...
Article
Semantic distinctions between "normal" aging, "pathological" aging (or age-related disease) and "premature" aging (otherwise known as segmental progeria) potentially confound important insights into the nature of each of the complex processes. Here we review a recent, unexpected discovery: the presence of longevity-associated characteristics typica...
Article
Full-text available
How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectat...
Article
Full-text available
Ku80 maintains the genome by repairing DNA double-strand breaks (DSBs) through nonhomologous end joining (NHEJ), a pathway that repairs nonspecific DSBs and Rag-1 Rag-2 (Rag)-specific DSBs. As a result, Ku80 deletion results in phenotypes characteristic of defective repair for both nonspecific DSBs (gamma-radiation hypersensitivity and genomic inst...
Data
Progeroid Features of CH/XPA Mice CH/XPA mice are shown relative to littermate controls at 2 mo of age displaying unusual daytime eating behavior and abnormal clasping of hind limbs in a tail-hanging test; and again at 5 mo of age displaying disturbed gait, loss of balance, and kyphosis. (3.0 MB WMV)

Citations

... Overall, regarding histologic subtype, obesity could be a potential risk factor of inflammatory and basal-like BC independently from menopausal status [13••, 20]. There is also preclinical evidence from mouse mammary tumors for connections between dietinduced obesity and both basal-like and luminal BC progression but not human epidermal growth factor receptor (HER)-2 and luminal B BC subtypes, despite the fact that these preclinical models do not fully represent human BC subtypes [11,21,22]. ...
... Thus, our patients had taken antipsychotic medicines much longer and may have had more side effects related to the change of sex hormones caused by long-term antipsychotic treatment. Moreover, recent studies reported that the hormonal changes during menopause increased abdominal obesity, insulin resistance and hyperplasia markedly [45][46][47] . Also, a previous study showed that menopausal women developed much more obesity and other metabolic abnormalities than non-menopausal women 48 . ...
... Importantly, peripheral administration of exogenous estrogen is sufficient for normal bodyweight to be restored [8,13,19]. Estrogen also has potential for increasing BAT sympathetic nerve discharge (SND) and BAT thermogenesis in females [2,11,17]. Several lines of evidence suggest that the presence of estrogen receptor alpha (Esr1) within the ventromedial nucleus of the hypothalamus (VMH) is implicated in the regulation of BAT SND. Adenovirus mediated knockout of Esr1 receptors in the VMH results in weight gain [12]. ...
... MMTV-Neu mice express wild-type, unactivated Neu in mammary tissue under the control of the mouse mammary tumor virus (MMTV) promoter 33 and develop focal mammary adenocarcinomas by 25-35 weeks of age 39 . To investigate the chemopreventive effects of V-125 in this preclinical model of HER2 + breast cancer 40,41 , MMTV-neu mice were fed control diet or V-125 in diet (30 mg/kg) starting at 10 weeks of age. V-125 significantly (p < 0.001) delayed initial tumor development compared to the control group (Fig. 3A), resulting in an approximately 10 week increase in mean time to tumor development (36.1 ± 7.8 weeks vs. control 26.5 ± 4.9 weeks). ...
... ERα suppressed fatty acid and glycerolipid synthesis by inhibiting mRNA and protein expression of ChREBP in pancreatic islet β-cells.13 Oestrogen, which opposed excessive lipid synthesis in the liver and gluconeogenesis, may partially occur from membrane ERα signalling, to suppress ChREBP and triglycerides in mature fat cells.14,33,34 Our data suggested that E2 treatmentpromoted nuclear translocation of ERα and dampened the binding between ChREBPα and ChREBPβ. ...
... It is known that male mice have greater weight gain than females and, therefore, are ideal for comparison focusing on white adipose tissue. In addition, several hormonal factors can regulate inflammatory pathways in females and promote differences in metabolic reproduction [89][90][91][92][93]. Therefore, studies involving the female animals were excluded, thus following the exclusive determination activity, since the study's primary objective covers the specific antiadipogenic mechanisms. ...
... The inverse relationship between alcohol consumption and diabetes was also found to be more pronounced in overweight than in normal-weight populations [50,54,55]. The protective effect of alcohol consumption which is more visible in women and overweight subjects is potentially explained by studies that have shown alcohol to be associated with enhanced insulin sensitivity [56]. Women have a genetically greater proportion of fat mass compared to men. ...
... Second, development-related risk factors are important. Different from longevity, increased risk of breast cancer for women in more developed countries could be due to the adaptation of high risk lifestyle and behaviors, such as delay in age of marriage, decline in breastfeeding [26], increases in alcohol use [27,28], exposure to secondhand smoking [29,30], high protein and fat diet [31], lack of physical activity [25,32], overweight and obese [33]. For example, official figures show that the average age of marriage reduced from 23.4 in the 1990s to 27.1 in the 2000s; rate of breast feeding declined from 67% in 1998 to 28% in 2014; there are significant increase in beef and pork and decline in vegetables [25]; 29.3% women drinking alcohol. ...
... The influence of alcohol on the risk of breast cancer is most often explained by the fact that alcohol affects the levels of circulating sex hormones, where high levels of oestrogen in the blood are associated with an elevated risk of breast cancer. Alcohol increases the concentration of oestrogen in the blood, rendering the oestrogen concentration particularly high in the middle of the menstrual cycle (27-38% higher than in abstainers) when the oestrogen levels are already high by nature; hence the conclusion that alcohol can contribute to the processes of neoplasia more strongly in adolescence than in adulthood [36]. Unfortunately, only a small percentage of the population is aware that alcohol has a different effect on the female body than on the male body, with the risk of negative consequences being several times greater in women. ...
... In response to stress, p53, acting in part by stimulating p21 transcription, induces a G 1 checkpoint to drive cells into quiescence (reversible G 1 arrest). In DNA repair defective mice, p53 is constitutively active (49) and essential for the rapid senescence of fibroblasts from those mice (50,51). Yet as noted above, p53 also suppresses the SASP in conjunction with rapamycin in human cells (45). ...