Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel

Schlaepfer, Isabel R.; Hitz, Carolyn A.; Gijón, Miguel A.; Bergman, Bryan C.; Eckel, Robert H.; Jacobsen, Britta M.

doi:10.1016/j.mce.2012.08.005

Cited by 65 publications

(78 citation statements)

References 64 publications

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“…These results are in agreement with our previous report, 12 where treatment with MPA leads to increased palmitate accumulation in triglycerides analyzed by chromatography methods. We observed a similar trend for the prostate cancer cell line LNCaP treated with R1881.…”

Section: Least-squares Fittingsupporting

confidence: 94%

“…10,11 Palmitic and oleic acids are abundantly made by the cancer cells in response to hormone treatment, and pharmacological inhibition of their synthesis has been shown to decrease cancer cell viability and resistance to chemotherapy agents. 12 Thus, accumulation of LDs inside cancer cells seems to be a hallmark of cancer metabolism and growth that can be exploited for biomarker discovery.…”

Section: Introductionmentioning

confidence: 99%

“…Lipid content is usually analyzed by using gas chromatography/mass spectroscopy, 12 but the cellular dynamics and the lipids distribution are lost during the homogenization process. Moreover, these techniques cannot be used in vivo or for live cell studies.…”

Section: Introductionmentioning

confidence: 99%

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Raman and coherent anti-Stokes Raman scattering microscopy studies of changes in lipid content and composition in hormone-treated breast and prostate cancer cells

et al. 2014

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Abstract. Increasing interest in the role of lipids in cancer cell proliferation and resistance to drug therapies has motivated the need to develop better tools for cellular lipid analysis. Quantification of lipids in cells is typically done by destructive chromatography protocols that do not provide spatial information on lipid distribution and prevent dynamic live cell studies. Methods that allow the analysis of lipid content in live cells are therefore of great importance. Using micro-Raman spectroscopy and coherent anti-Stokes Raman scattering (CARS) microscopy, we generated a lipid profile for breast (T47D, MDA-MB-231) and prostate (LNCaP, PC3) cancer cells upon exposure to medroxyprogesterone acetate (MPA) and synthetic androgen R1881. Combining Raman spectra with CARS imaging, we can study the process of hormone-mediated lipogenesis. Our results show that hormone-treated cancer cells T47D and LNCaP have an increased number and size of intracellular lipid droplets and higher degree of saturation than untreated cells. MDA-MB-231 and PC3 cancer cells showed no significant changes upon treatment. Principal component analysis with linear discriminant analysis of the Raman spectra was able to differentiate between cancer cells that were treated with MPA, R1881, and untreated. © The Authors.Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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Section: Least-squares Fittingsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Raman and coherent anti-Stokes Raman scattering microscopy studies of changes in lipid content and composition in hormone-treated breast and prostate cancer cells

et al. 2014

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“…This finding suggests a potential for using metabolite information for breast cancer diagnosis and tumor margin identification (61,62). Here, we demonstrate an MS-based methodology for using lipidomic information to distinguish cancerous from noncancerous tissue and to delineate tumor boundaries.…”

mentioning

confidence: 88%

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis

Calligaris

Caragacianu

Liu

et al. 2014

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

213

202

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Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used.Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MSbased method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.B reast cancer is the most commonly diagnosed carcinoma in women in the United States and Western countries. Breast conservation surgery (BCS) has become the preferred treatment option for many women with early-stage breast cancer (1). BCS entails resection of the tumor, with a clean margin of normal tissue around it. Surgery is usually followed by radiation therapy. Results from seven large randomized prospective studies, with the largest two having over 20 y of follow-up, have shown equal survival when comparing BCS coupled with whole-breast radiation and mastectomy (2, 3).Normally, breast surgeons aim to remove a patient's tumor, along with a rim of normal tissue that is free of cancer. Preoperative mammography, ultrasonography, or MRI may be used by the surgeon to guide adequate resection (4-6). Despite numerous improvements in imaging and surgical technique, the need for reexcision to achieve complete tumor resection in the United States typically ranges from 20-40% (7-15), and has been reported as being as high as 60% (16). The importance of reexcision is underscored by numerous studies, which have shown that incomplete resection of tumor and positive margins are associated with increased locoregional recurrence compared with negative margins (12,(17)(18)(19)(20). Furthermore, the landmark meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group (18, 21) directly linked local recurrence to survival, placing great emphasis on the surgeon's role in minimizing local recurrence by obtaining adequate margins.Breast tumor reexcisions are accompanied by a number of undesirable problems: The completion of therapy is delayed, infection rates are increased, cost is increased, there can be a negative psychological impact on the patient, and there can be diminished aesthetic outcomes (22-24). The development of an intraoperative technique that allows the fast and accurate ident...

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“…Presumably, the amounts of de novo synthesized fatty acids correlate with the levels of FASN protein. In cancer cells, FASN expression is regulated by the HER2/Neu and PI3K signaling pathways, steroid hormones, and genomic amplification [20,34,37,42]; however, the spectrum of fatty acid products and the kinetics of the FASN reaction can be altered by effector proteins [21,32]. Interestingly, the effects of metformin on miR193b and FASN were only observed when cells were grown in media containing physiologic glucose levels (5 mM) compared to high glucose (17 mM).…”

Section: Diabetes Breast Cancer and Metforminmentioning

confidence: 99%

FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

Wellberg

Anderson

2014

HORM CANC

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Diabetes, Breast Cancer, and MetforminEmerging data suggest that metformin treatment is associated with reduced breast cancer incidence and mortality for individuals with type II diabetes [7,6,17]. For years, many studies have been done to investigate the possible direct and indirect effects of metformin on cancers of various origins. In diabetic patients, metformin improves metabolic function by promoting muscle glucose uptake and lowering hepatic gluconeogenesis [14,15,36]. In cultured cancer and normal cells, metformin has pleiotropic effects, including decreasing mitochondrial electron transport complex I activity, increasing the cellular AMP to ATP ratio, and activating the AMPK signaling pathway. The consequence of this is reduced protein translation, DNA synthesis, and cell proliferation. In isolated cancer stem-like cells (CSC), metformin's targets range from inflammation [13], to micro-RNAs [1], to the synthesis of nucleotide triphosphates [16]. The diversity of responses elicited by metformin from different tissues and from the specific cell types within those tissues suggests that metformin may be a valuable therapeutic for the treatment of a variety of cancers at many stages of tumor progression. Indeed, scores of clinical trials aiming to investigate the therapeutic effects of metformin for patients with cancer are either planned or ongoing. For breast cancer, large trials are open for patients with early-stage disease (NCT01101438) and metastatic disease (NCT01310231). The results of these trials are highly anticipated and will likely answer many lingering questions about the efficacy of metformin against cancer in nondiabetic patients. Short-term trials have also been conducted to evaluate the effects of metformin on breast tumor cell proliferation (NCT00897884) and tumor cell metabolism (NCT01266486).In this issue, Wahdan-Alaswad et al. demonstrate that in ER/PR/HER2-negative (triple negative (TN)) breast cancer cells metformin treatment targets fatty acid synthase (FASN) through a miR193b-dependent mechanism. Specifically, in TN breast cancer cells, metformin upregulated miR193b, which directly targeted the FASN mRNA resulting in decreased FASN protein levels. This was associated with reduced proliferation and increased apoptosis. Gene expression profiling also revealed changes in other metabolic enzymes, including members of the cholesterol biosynthesis pathway, suggesting that metformin may impact cancer cell lipid metabolism networks at multiple nodes. One limitation of this study is that the levels of cellular fatty acids were not quantified. Presumably, the amounts of de novo synthesized fatty acids correlate with the levels of FASN protein. In cancer cells, FASN expression is regulated by the HER2/Neu and PI3K signaling pathways, steroid hormones, and genomic amplification [20,34,37,42]; however, the spectrum of fatty acid products and the kinetics of the FASN reaction can be altered by effector proteins [21,32]. Interestingly, the effects of metformin on miR193b and FASN were only observe...

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Progestin modulates the lipid profile and sensitivity of breast cancer cells to docetaxel

Cited by 65 publications

References 64 publications

Raman and coherent anti-Stokes Raman scattering microscopy studies of changes in lipid content and composition in hormone-treated breast and prostate cancer cells

Raman and coherent anti-Stokes Raman scattering microscopy studies of changes in lipid content and composition in hormone-treated breast and prostate cancer cells

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis

FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

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