Browsing by Author "Mentoor, Ilze"

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    Chemoresistance : intricate interplay between breast tumor cells and adipocytes in the tumor microenvironment
    (Frontiers Media, 2018-12-11) Mentoor, Ilze; Engelbrecht, Anna-Mart; Van Jaarsveld, Paul J.; Nell, Theo A.; Vella, Veronica
    Excess adipose tissue is a hallmark of an overweight and/or obese state as well as a primary risk factor for breast cancer development and progression. In an overweight/obese state adipose tissue becomes dysfunctional due to rapid hypertrophy, hyperplasia, and immune cell infiltration which is associated with sustained low-grade inflammation originating from dysfunctional adipokine synthesis. Evidence also supports the role of excess adipose tissue (overweight/obesity) as a casual factor for the development of chemotherapeutic drug resistance. Obesity-mediated effects/modifications may contribute to chemotherapeutic drug resistance by altering drug pharmacokinetics, inducing chronic inflammation, as well as altering tumor-associated adipocyte adipokine secretion. Adipocytes in the breast tumor microenvironment enhance breast tumor cell survival and decrease the efficacy of chemotherapeutic agents, resulting in chemotherapeutic resistance. A well-know chemotherapeutic agent, doxorubicin, has shown to negatively impact adipose tissue homeostasis, affecting adipose tissue/adipocyte functionality and storage. Here, it is implied that doxorubicin disrupts adipose tissue homeostasis affecting the functionality of adipose tissue/adipocytes. Although evidence on the effects of doxorubicin on adipose tissue/adipocytes under obesogenic conditions are lacking, this narrative review explores the potential role of obesity in breast cancer progression and treatment resistance with inflammation as an underlying mechanism.
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    Chemoresistance in a breast cancer animal model: the role of obesity and inflammation
    (Stellenbosch : Stellenbosch University, 2019-12) Mentoor, Ilze; Nell, Theo A.; Engelbrecht, Anna-Mart; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Background: Globally an increase in obesity incidence represent a major health concern amongst a rising incidence of impaired treatment outcomes of breast cancer patients. Adipose tissue and/or adipocytes, in the tumour microenvironment serve as an exogenous energy source for the survival of breast cancer cells, especially since adipose tissue is abundant in breast tissue. Breast cancer cells modulate lipid metabolism (de novo fatty acid synthesis and lipolysis), by altering the secretion of adipokines through adipocytes, resulting in the release of free fatty acids to provide energy substrates for breast cancer cells to sustain its high proliferation demand for survival. Evidence on the role of obesity and lipid metabolism especially fatty acids in breast cancer treatment resistance is lacking. This motivates investigation to identify and understand the underlying physiological and molecular mechanisms by which chemotherapeutic treatment resistance is achieved. We therefore hypothesise that obesity-induced inflammation alters lipid metabolism in adipose tissue/adipocytes and contribute to the development of doxorubicin chemotherapeutic treatment resistance in breast cancer cells. Methods: A diet induced obesity animal model was established by feeding female C57BL6 mice a high fat diet for 12 weeks. After developing the diet induced obesity phenotype, breast tumour xenographs were induced by subcutaneous inoculation in the fourth mammary gland with E0771 triple negative breast cancer cells.Once tumours became palpable, mice received either vehicle treatment (Hanks balance salt solution) or doxorubicin treatment (cumulative dose of 12 mg/kg). Plasma inflammatory markers, fatty acid profiles and protein expression of lipid metabolism markers (de novo fatty acid synthesis and lipolysis) was determined in mammary adipose and tumour tissue. To validate the in vivo model findings, we developed an in vitro model using a conditioned media approach. A human adipose tissue derived stem cell line was used for the differentiation of mature adipocytes after which conditioned media was collected to assess the paracrine effect between adipocytes and doxorubicin treated MDA-MB-231 triple negative breast cancer cells. Cell viability was assessed with WST-1 assays. Western blots were used to determined alterations in protein expression of apoptotic and lipid metabolism markers (de novo fatty acid synthesis and lipolysis). An Inflammatory marker as well as free fatty acid profile was also analysed in treatment conditioned media. Results: Diet induced obesity significantly increased tumour growth and decreased doxorubicin treatment efficacy in E0771 triple negative breast tumours (p<0.0001), resulting in treatment resistance. Our findings also showed that diet induced obesity supressed de novo fatty acid synthesis (decreased SCD-1) and lipolysis (decreased HSL) in mammary adipose tissue of doxorubicin treated mice. Conversely an increase in de novo fatty acid synthesis (increased SCD-1) and lipolysis (increased ATGL) was found in tumour tissue, leading to significant changes in FAs composition of both tissues. Diet induced obesity also significantly increased plasma leptin (p=0.025) and resistin levels (p=0.046) and increased NFĸB protein expression in mammary fat of doxorubicin treated mice, thereby inducing systemic and local inflammation. Furthermore, we also report that adipocytes promoted acquired breast cancer treatment resistance by significantly increasing the cell viability of doxorubicin treated MDA-MB-231 triple negative breast cancer cells (Dox+CM vs Dox, p=<0.0001). This was achieved by attenuating doxorubicin’s efficacy to induce apoptosis (decreased cleaved-caspase-3, p<0.05), in a paracrine manner. Adipocytes also induced inflammation (increased leptin and MCP-1) as well as lipolysis (increased HSL) in doxorubicin treated breast cancer cells (Dox vs Dox+CM p=0.03), thereby altering the free fatty acid profile of breast cancer cells. Conclusion: Our data suggest that adipose tissue/adipocytes significantly contribute to treatment resistance in triple negative breast cancer cells. We have demonstrated in both in vivo and in vitro models that adipose tissue/adipocytes secretory factors induce inflammation in the breast tumour microenvironment, which leads to the induction of lipolysis in triple negative breast cancer cells. This resulted in altered metabolic behaviour i.e. increased free fatty acid utilization, which can be utilized as energy substrates or induce lipid saturation in order confer to acquired treatment resistance by evading apoptosis We propose that this could be a novel mechanism by which adipose tissue/adipocytes within the tumour microenvironment can contribute to the development of breast cancer treatment resistance under obesogenic conditions. This study also significantly contributed to the identification and understanding of molecular mechanisms underlying breast cancer treatment resistance in obese patients.
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    Decreased efficacy of doxorubicin corresponds with modifications in lipid metabolism markers and fatty acid profiles in breast tumors from obese vs. lean mice
    (Frontiers Media, 2018-03-17) Mentoor, Ilze; Nell, Theo A.; Emjedi, Zaakiyah; Van Jaarsveld, Paul J.; De Jager, Louis; Engelbrecht, Anna-Mart; Sotgia, Federica
    Breast cancer cells modulate lipid and fatty acid metabolism to sustain proliferation. The role of adipocytes in cancer treatment efficacy remains, however, to be fully elucidated. We investigated whether diet-induced obesity (DIO) affects the efficacy of doxorubicin treatment in a breast tumor-bearing mouse model. Female C57BL6 mice were fed a high fat or low fat diet for the full duration of the study (12 weeks). After 8 weeks, mice were inoculated with E0771 triple-negative breast cancer cells in the fourth mammary gland to develop breast tumor allographs. Tumor-bearing mice received either vehicle (Hank's balanced salt solution) or doxorubicin (chemotherapy). Plasma inflammatory markers, tumor, and mammary adipose tissue fatty acid composition, as well as protein expression of lipid metabolism markers were determined. The high fat diet (HFD) attenuated the treatment efficacy of doxorubicin. Both leptin and resistin concentrations were significantly increased in the HFD group treated with doxorubicin. Suppressed lipogenesis (decreased stearoyl CoA-desaturase-1) and lipolysis (decreased hormone-sensitive lipase) were observed in mammary adipose tissue of the DIO animals, whereas increased expression was observed in the tumor tissue of doxorubicin treated HFD mice. Obesogenic conditions induced altered tissue fatty acid (FA) compositions, which reduced doxorubicin's treatment efficacy. In mammary adipose tissue breast cancer cells suppressed the storage of FAs, thereby increasing the availability of free FAs and favored inflammation under obesogenic conditions.
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    Metabolic syndrome and body shape predict differences in health parameters in farm working women
    (BioMed Central, 2018-04-04) Mentoor, Ilze; Kruger, Maritza; Nell, Theo A.
    Background: Sufficient evidence associate body shape to detrimental lifestyle diseases including the metabolic syndrome (MetS). The prevalence of the MetS, as well as effects of the MetS and body shape on body composition, insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP) and sex hormone parameters were investigated in a female farm worker population in the Western Cape. Methods: Women between the ages of 20–60 years were classified according to the International Diabetes Federation’s definition of the MetS. Assessments included body shape (android/gynoid), blood pressure, anthropometric, bioelectrical impedance analyses and blood analyses for fasting glucose and insulin, lipid profile, IGF-1, CRP, and sex hormone parameters. Results: The prevalence of the MetS was 52%, with abdominal obesity 68.8%, hypertension 66.4% and low high density lipoprotein-cholesterol (HDL-c) levels (64.1%) being the more prevalent MetS risk factors. The MetS, irrespective of body shape, was found to be associated with body mass index (p < 0.01), fat mass (%) (p < 0.01), waist circumference (p < 0.001), HDL-c (p < 0.001), systolic blood pressure (p < 0.05) and diastolic blood pressure (p < 0.01). No significant differences were observed for IGF-1, CRP and sex hormone parameters. Conclusion: The prevalence of the MetS and its individual risk factors were found to be significantly high in this female farm worker population. Additionally, the study showed that the MetS, body shape and/or both could predict differences in body composition, physiological and biochemical parameters in women.