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Lundberg, P., Forsgren, M. F., Tellman, J., Kihlberg, J., Rzepecka, A. & Dabrosin, C. (2022). Breast density is strongly associated with multiparametric magnetic resonance imaging biomarkers and pro-tumorigenic proteins in situ. British Journal of Cancer, 127, 2025-2033
Open this publication in new window or tab >>Breast density is strongly associated with multiparametric magnetic resonance imaging biomarkers and pro-tumorigenic proteins in situ
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2022 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 127, p. 2025-2033Article in journal (Refereed) Published
Abstract [en]

Background High mammographic density is an independent risk factor for breast cancer by poorly understood molecular mechanisms. Women with dense breasts often undergo conventional magnetic resonance imaging (MRI) despite its limited specificity, which may be increased by diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) and contrast. How these modalities are affected by breast density per se and their association with the local microenvironment are undetermined. Methods Healthy postmenopausal women attending mammography screen with extremely dense or entirely fatty breasts underwent multiparametric MRI for analyses of lean tissue fraction (LTF), ADC and perfusion dynamics. Microdialysis was used for extracellular proteomics in situ. Results Significantly increased LTF and ADC and delayed perfusion were detected in dense breasts. In total, 270 proteins were quantified, whereof 124 related to inflammation, angiogenesis, and cellular growth were significantly upregulated in dense breasts. Most of these correlated significantly with LTF, ADC and the perfusion data. Conclusions ADC and perfusion characteristics depend on breast density, which should be considered during the implementation of thresholds for malignant lesions. Dense and nondense breasts are two essentially different biological entities, with a pro-tumorigenic microenvironment in dense breasts. Our data reveal several novel pathways that may be explored for breast cancer prevention strategies.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-189079 (URN)10.1038/s41416-022-01976-3 (DOI)000859665200002 ()36138072 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2018/464]; Swedish Research Council [2018-02584]; LiU-Cancer project grant; ALF of Linkoping University Hospital; Linkoping University

Available from: 2022-10-11 Created: 2022-10-11 Last updated: 2024-02-21Bibliographically approved
Mijic, S. & Dabrosin, C. (2021). Platelet Activation In Situ in Breasts at High Risk of Cancer: Relationship with Mammographic Density and Estradiol. Journal of Clinical Endocrinology and Metabolism, 106(2), 485-500
Open this publication in new window or tab >>Platelet Activation In Situ in Breasts at High Risk of Cancer: Relationship with Mammographic Density and Estradiol
2021 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 2, p. 485-500Article in journal (Refereed) Published
Abstract [en]

Context: High mammographic density in postmenopausal women is an independent risk factor for breast cancer by undetermined mechanisms. No preventive therapy for this risk group is available. Activated platelets release growth factors that modulate the microenvironment into a protumorigenic state. Estrogens may affect the risk of breast cancer and platelet function. Whether platelets are activated in situ in breast cancer or in normal breast tissue at high risk of breast cancer and the association to estradiol remains elusive. Objective: To investigate whether platelets are activated in situ in breast cancers and in dense breast tissue of postmenopausal women and explore correlations between estradiol, released platelet factors, and inflammatory proteins. Setting and design: Sampling of in vivo proteins was performed using microdialysis in a total of 71 women: 10 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 premenopausal women. Results: Our data demonstrate increased levels of coagulation factors in dense breast tissue similar to that found in breast cancers, indicating excessive platelet activation. Premenopausal breasts exhibited similar levels of coagulation factors as postmenopausal dense breasts. Out of 13 coagulations factors that were upregulated in dense breasts, 5 exhibited significant correlations with estradiol, both locally in the breast and systemically. In breast tissue, positive correlations between coagulation factors and key inflammatory proteins and matrix metalloproteinases were detected. Conclusions: Breast density, not estradiol, is the major determinant of local platelet activation. Inactivation of platelets may be a therapeutic strategy for cancer prevention in postmenopausal women with dense breasts.

Place, publisher, year, edition, pages
ENDOCRINE SOC, 2021
Keywords
microdialysis; mammary gland; inflammation; mammography
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-175430 (URN)10.1210/clinem/dgaa820 (DOI)000759115900024 ()33180937 (PubMedID)
Note

Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [2018/464]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-02584]; LiU-Cancer; ALF of Linkoping University Hospital

Available from: 2021-05-04 Created: 2021-05-04 Last updated: 2024-02-21Bibliographically approved
Abrahamsson, A., Vazquez Rodriguez, G. & Dabrosin, C. (2020). Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen. Cancer Research, 80(20), 4487-4499
Open this publication in new window or tab >>Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen
2020 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 20, p. 4487-4499Article in journal (Refereed) Published
Abstract [en]

Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.

Place, publisher, year, edition, pages
Philadelphia, PA, United States: AMER ASSOC CANCER RESEARCH, 2020
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-171382 (URN)10.1158/0008-5472.CAN-20-1705 (DOI)000582353000017 ()32855207 (PubMedID)
Note

Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [2018/464]; Swedish Research CouncilSwedish Research Council [2018-02584]; LiU-Cancer; ALF of Linkoping University Hospital

Available from: 2020-11-15 Created: 2020-11-15 Last updated: 2024-02-21Bibliographically approved
Vazquez Rodriguez, G., Abrahamsson, A., Jensen, L. D. & Dabrosin, C. (2018). Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8. Frontiers in Immunology, 9, 1-17, Article ID 1767.
Open this publication in new window or tab >>Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8
2018 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, p. 1-17, article id 1767Article in journal (Refereed) Published
Abstract [en]

Fat is a major tissue component in human breast cancer (BC). Whether breast adipocytes (BAd) affect early stages of BC metastasis is yet unknown. BC progression is dependent on angiogenesis and inflammation, and interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are key regulators of these events. Here, we show that BAd increased the dissemination of estrogen receptor positive BC cells (BCC) in vivo in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BCC such as estrogen receptor negative was unaffected. While anti-VEGF and anti-IL-8 exhibited equal inhibition of angiogenesis at the primary tumor site, anti-IL-8 reduced BCC dissemination whereas anti-VEGF had minor effects on this early metastatic event. Mechanistically, overexpression of cell-adhesion molecules in BCC and neutrophils via IL-8 increased the dissemination of BCC. Importantly, the extracellular in vivo levels of IL-8 were 40-fold higher than those of VEGF in human BC. Our results suggest that IL-8 is a clinical relevant and promising therapeutic target for human BC.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
breast cancer, microdialysis, zebrafish, angiogenesis, inflammation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-150059 (URN)10.3389/fimmu.2018.01767 (DOI)000440193400002 ()
Funder
Swedish Cancer Society, 2015/309Swedish Research Council, 2013-2457
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2024-02-21
Vazquez Rodriguez, G., Abrahamsson, A., Jensen, L. & Dabrosin, C. (2017). Estradiol promotes breast cancer cell migration via recruitment and activation of neutrophils. Cancer Immunology research, 5(3), 234-247, Article ID 28159748.
Open this publication in new window or tab >>Estradiol promotes breast cancer cell migration via recruitment and activation of neutrophils
2017 (English)In: Cancer Immunology research, ISSN 2326-6066, Vol. 5, no 3, p. 234-247, article id 28159748Article in journal (Refereed) Published
Abstract [en]

Estradiol (E2) plays a key role in breast cancer progression. Most breast cancer recurrences express the estrogen receptor (ER), but nearly 50% of patients are resistant to antiestrogen therapy. Novel therapeutic targets of ER-positive breast cancers are needed. Protumoral neutrophils expressing the lymphocyte function-associated antigen 1 (LFA-1) integrin may mediate cancer metastasis, and TGFβ1 is the major chemoattractant for neutrophils. The role of E2 in neutrophil–ER+ breast cancer cell interactions is unknown. We studied this in vivo using murine breast cancers in immunocompetent mice and human breast cancers in nude mice. Cell dissemination was evaluated in a zebrafish model, and microdialysis of breast cancer patients was performed. In vitro studies were done with mammosphere cultures of breast cancer cells and human neutrophils. We found that E2 increased the number of LFA-1+ neutrophils recruited to the invasive edge of mouse tumors, increased TGFβ1 secretion and promoted neutrophil infiltration in mammospheres, and induced overexpression of LFA-1 in neutrophils. In zebrafish, in the presence of E2, neutrophils increased dissemination of ER+ breast cancer cells via LFA-1 and TGFβ1, thus causing noninvasive cancer cells to be highly metastatic. Time-lapse imaging in zebrafish revealed close interactions of neutrophils with cancer cells, which drove breast cancer metastasis. We also found that extracellular TGFβ1 was overproduced in human breast cancer tissue compared with adjacent normal breast tissue. Thus, E2 can regulate immune/cancer cell interactions in tumor microenvironments. Our results indicate that extracellular TGFβ1 is a relevant target in human breast cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-135330 (URN)10.1158/2326-6066.CIR-16-0150 (DOI)000396023000006 ()28159748 (PubMedID)
Funder
Swedish Cancer Society, 2015/309Swedish Research Council, 2013-2457Linköpings universitet
Note

Funding agencies: Swedish Cancer Society [2015/309]; Swedish Research Council [2013-2457]; LiU-Cancer; Research Funds of Linkoping University Hospital

Available from: 2017-03-13 Created: 2017-03-13 Last updated: 2024-02-21
Abrahamsson, A., Rzepecka, A. & Dabrosin, C. (2017). Increased nutrient availability in dense breast tissue of postmenopausal women in vivo. Scientific Reports, 7, Article ID 42733.
Open this publication in new window or tab >>Increased nutrient availability in dense breast tissue of postmenopausal women in vivo
2017 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 42733Article in journal (Refereed) Published
Abstract [en]

Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-135389 (URN)10.1038/srep42733 (DOI)000394294800001 ()28198437 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2015/309]; Swedish Research Council [2013-2457]; LiU-Cancer; Linkoping University Hospital

Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2024-02-21
Morad, V., Abrahamsson, A., Kjölhede, P. & Dabrosin, C. (2016). Adipokines and Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo - Correlations and Attenuation by Dietary Flaxseed. Journal of mammary gland biology and neoplasia, 21(1-2), 69-76
Open this publication in new window or tab >>Adipokines and Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo - Correlations and Attenuation by Dietary Flaxseed
2016 (English)In: Journal of mammary gland biology and neoplasia, ISSN 1083-3021, E-ISSN 1573-7039, Vol. 21, no 1-2, p. 69-76Article in journal (Refereed) Published
Abstract [en]

Exposure to sex steroids increases the risk of breast cancer but the exact mechanisms are yet to be elucidated. Events in the microenvironment are important for carcinogenesis. Diet containing phytoestrogens can affect the breast microenvironment and alter the risk of breast cancer. It has previously been shown that estrogen regulates extracellular levels of leptin, adiponectin, and VEGF in normal breast tissue in vivo. Whether these proteins correlate in breast tissue in vivo or if diet addition of flaxseed, a major source of phytoestrogens in Western diets, alters adipokine levels in breast tissue are unknown. We used microdialysis to sample proteins of normal human breast tissue and abdominal subcutaneous fat in situ in 34 pre-and postmenopausal women. In vitro, co-culture of breast cancer cells and primary human adipocytes was used. In vivo, in normal breast tissue, a significant positive correlation between VEGF and leptin was detected. No correlations were found in fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. The levels of leptin decreased and adiponectin increased after a dietary addition of 25 g of flaxseed/day for one menstrual cycle. We conclude that VEGF and leptin correlate significantly in normal human breast tissue in vivo and that dietary addition of flaxseed affect adipokine levels in the breast.

Place, publisher, year, edition, pages
SPRINGER/PLENUM PUBLISHERS, 2016
Keywords
Flaxseed; Diet; Microdialysis; Estrogen; Leptin; Adiponectin
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130433 (URN)10.1007/s10911-016-9352-9 (DOI)000379327000009 ()27059487 (PubMedID)
Available from: 2016-08-07 Created: 2016-08-05 Last updated: 2024-02-21
Dabrosin, C. (2015). An overview of pregnancy and fertility issues in breast cancer patients. Annals of Medicine, 47(8), 673-678
Open this publication in new window or tab >>An overview of pregnancy and fertility issues in breast cancer patients
2015 (English)In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 47, no 8, p. 673-678Article, review/survey (Refereed) Published
Abstract [en]

Breast cancer is one of the most common malignancies of women in the reproductive years. In the Western world there is a trend towards delaying pregnancy to later in life, and in combination with an increased incidence of breast cancer an increased number of women are diagnosed with breast cancer before they have completed their reproductive plans. In addition, breast cancer during pregnancy may affect an increased number of women as the childbearing years are delayed. The survival rate after breast cancer has improved during the last decades, and many young breast cancer survivors will consider a pregnancy subsequent to the completion of adjuvant breast cancer therapy. Traditionally, many women are advised against a pregnancy due to a fear of increased risk of recurrence, especially women with estrogen receptor-positive breast cancer. Due to feasibility issues, evidence from large prospective randomized trials is missing regarding the safety of pregnancy after breast cancer. Today guidelines are based on cohort studies and population-based registry evidence with its limitations. Overall, data suggest that pregnancy after breast cancer therapy is safe, and the current evidence is summarized in this overview.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2015
Keywords
Breast cancer; estrogen receptor; fertility; mammary cancer; pregnancy
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123841 (URN)10.3109/07853890.2015.1096953 (DOI)000366590600005 ()26542739 (PubMedID)
Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2024-02-21
Wang, Z., Dabrosin, C., Yin, X., Fuster, M. M., Arreola, A., Rathmell, W. K., . . . Jensen, L. D. (2015). Broad targeting of angiogenesis for cancer prevention and therapy. Seminars in Cancer Biology, S1044-579X(15), 00002-00004
Open this publication in new window or tab >>Broad targeting of angiogenesis for cancer prevention and therapy
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2015 (English)In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. S1044-579X, no 15, p. 00002-00004Article, review/survey (Refereed) Published
Abstract [en]

Deregulation of angiogenesis - the growth of new blood vessels from an existing vasculature - is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Angiogenesis Cancer Phytochemicals Treatment Anti-angiogenic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-115783 (URN)10.1016/j.semcancer.2015.01.001 (DOI)000366619400011 ()25600295 (PubMedID)
Note

Funding agencies: Swedish Society for Medical Research; Goesta Fraenkel Foundation; Ake Wibergs Foundation; Ollie och Elof Ericssons Foundation; Karolinska Institute; Linkoping University; University of Glasgow; Beatson Oncology Center Fund; Cancer Research UK grant

Available from: 2015-03-19 Created: 2015-03-19 Last updated: 2024-02-21
Svensson, S., Abrahamsson, A., Vazquez Rodriguez, G., Olsson, A.-K., Jensen, L., Cao, Y. & Dabrosin, C. (2015). CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clinical Cancer Research, 21(16), 3794-3805
Open this publication in new window or tab >>CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
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2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 16, p. 3794-3805Article in journal (Refereed) Published
Abstract [en]

Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-122122 (URN)10.1158/1078-0432.CCR-15-0204 (DOI)000361909100027 ()25901081 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2009/799]; Swedish Research Council [2010-3458]; LiU-Cancer; Linkoping University Hospital

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2024-02-21
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ORCID iD: ORCID iD iconorcid.org/0000-0001-7191-0018

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