bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-04-15: Ethinylestradiol treatment downregulates ER and upregulates PgR; Immunohistochemical analysis in postmenopausal breast cancer tissues after prior long-term estrogen-deprivation therapy
Authors: Iwase Hirotaka , Omoto Yoko , Takeshita Takashi , Yamamoto-Ibusuki Mutsuko , Hayashi Mitsuhiro , Sueta Aiko , Fujiwara Saori , Yamamoto Yutaka
Published: May 2015

Background: Estrogen receptor (ER) positive breast cancer can often be treated by hormone therapy; however a certain population of ER-positive patients becomes resistant to hormone therapy after long-term hormone treatment. Ethinylestradiol (EE2) is a derivative of estrogen which has shown promising effects on in these patients. Methods: We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well-known breast cancer-related factors by analyzing their gene expression and by immunohistochemistry. Of the 6 patients, 5 responded but one patient did not.

Results: Before EE2 treatment, staining for both ER and androgen receptor (AR) was strong in the nucleus, with weak staining of the progesterone receptor (PgR). EE2 treatment significantly down-regulated ER and up-regulated PgR while nuclear and cytosolic AR were oppositely down- and up-regulated, respectively, by EE2. Cytosolic staining of BRCA1 was significantly up-regulated by EE2 whereas nuclear staining tended to decrease. Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non-responder following EE2 treatment. Conclusion: Our observations revealed that EE2 activated ER downstream genes, although it did not stimulate cell growth. This suggests that hormone resistant cells might receive growth signals from a non-genomic pathway and this may be reflected in their sensitivity to EE2 treatment.

Citation Format: Hirotaka Iwase, Yoko Omoto, Takashi Takeshita, Mutsuko Yamamoto-Ibusuki, Mitsuhiro Hayashi, Aiko Sueta, Saori Fujiwara, Yutaka Yamamoto. Ethinylestradiol treatment downregulates ER and upregulates PgR; Immunohistochemical analysis in postmenopausal breast cancer tissues after prior long-term estrogen-deprivation therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-15.
Abstract P3-04-16: Estrogen receptor β agonists reduce breast cancer tumor growth in syngeneic mouse models
Authors: Samayoa Cathy , Krishnegowda Naveen K , Vadlamudi Ratna K , Tekmal Rajeshwar R
Published: May 2015

The estrogen receptors (ER) play a significant role in breast cancer, with the majority of breast cancers expressing estrogen receptor alpha (ERα) and depending on its signaling. ERα has proliferative function, however, estrogen receptor beta (ERβ) has anti-proliferative functions. Recently, several selective ERβ agonists have been identified. The objective of this study was to determine the effectiveness of ERβ agonists in inhibiting the growth of distinct breast cancer cells both in-vitro and in-vivo, and to determine the mechanisms involved. The mouse mammary tumor cell lines, D2A1 and MM51, express both ERα and ERβ. Specifically D2A1 cells are dependent on estrogen for growth and have increased expression of aromatase. Additionally, D2A1 cells are very aggressive and highly metastatic; representing a good model of breast cancer progression. MM51 cells are Her2/neu positive and are an adequate model to study the crosstalk between growth factors and ER signaling. Syngeneic mouse tumor models were used to incorporate an intact immune system which plays a role in the tumor’s microenvironment. Our in-vitro studies demonstrate that ERβ agonists significantly inhibit cell growth in a dose dependent manner. Our syngeneic studies show that, in-vivo, ERβ agonists effectively reduce tumor volume and inhibit tumor progression. This study reveals that in addition to acting on ERβ, these agonists reduce the expression of ERα at both the mRNA and protein level, therefore modulating the ratio of ERα to ERβ. Additionally, treatment with ERβ agonists results in increases apoptosis through increased p53 expression, and cell cycle arrest through p27 and cyclin D1. Together, these studies demonstrate the therapeutic potential of ERβ agonists for the treatment of breast cancer.

Citation Format: Cathy Samayoa, Naveen K Krishnegowda, Ratna K Vadlamudi, Rajeshwar R Tekmal. Estrogen receptor β agonists reduce breast cancer tumor growth in syngeneic mouse models [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-16.
Abstract P3-05-11: Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer
Authors: Shajahan-Haq Ayeasha N , Demo Susan , Clarke Robert
Published: May 2015

About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens (e.g.,Tamoxifen; TAM) are often used to treat ER+ breast cancer but breast cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Endocrine resistant cells survive antiestrogen treatment by initiating a pro-survival pathway mediated by an evolutionary conserved process call the unfolded protein response (UPR) within the endoplasmic reticulum. Cellular stress induced by therapeutics can be initiated by the UPR leading to a pro-survival response in the short-term and a pro-death response in the long-term, depending on the magnitude of the stress signal. Our studies show that antiestrogens can decrease glucose uptake in ER+ breast cancer cells, and in glucose-deprived conditions, presence of glutamine in the media can trigger the UPR through GRP78-IRE1a. Subsequently, a glutamine-dependent pathway can induce cell death via GRP78-IREa-JNK-CHOP and survival in others via GRP78-IRE1a-XBP1. Glutamine metabolites such as glutamate (essential substrate for many vital cellular processes) and proline (substrate for collagen production) are significantly elevated in endocrine resistant cells. Knockdown of glutaminase (GLS1) with siRNA or small molecule inhibitor, CB-839, significantly decreased cell proliferation in endocrine resistant cells compared with sensitive cells within 48 h. Moreover, cell lines derived from endocrine resistant cells that are grown in glucose-free media are significantly more sensitive to CB-839 compared with their respective controls, indicating an increased dependency on glutamine. Glutamine may offer an alternate source of energy and raw materials in periods of glucose deprivation, and in endocrine resistant cells, this adaptive pro-survival cellular metabolic mechanism is up-regulated. Thus, CB-839 may be a potent anti-cancer agent in treating antiestrogen resistant breast cancers.

Citation Format: Ayeasha N Shajahan-Haq, Susan Demo, Robert Clarke. Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-11.
Abstract P3-05-23: Novel, non-uterotrophic, selective estrogen mimics cause regression of tamoxifen-resistant breast cancer in 2D and 3D cultures and in mouse xenograft models
Authors: Thatcher Gregory RJ , Xiong Rui , Patel Hitisha K , Zhao Jiong , Liang Xiao , Wang Yue-ting , Molloy Mary Ellen , Tonetti Debra
Published: May 2015

Prior to the advent of tamoxifen therapy, estradiol (E2) and the ER agonist, diethylstilbestrol, showed efficacy in the clinical in therapeutic treatment of breast cancer. The adverse effects of these therapeutic options led to discontinuation, despite tamoxifen itself sharing the adverse effect of uterine growth. The perceived therapeutic action of tamoxifen in countering the proliferative actions of E2 at the estrogen receptor (ER) in endocrine-sensitive breast tissues is not entirely compatible with the therapeutic actions of E2 itself in breast cancer, and points to a more complex role for ER. Tamoxifen is the standard of care for many patients with ER+ breast cancer; however significantly, 30-50% of women are resistant to tamoxifen therapy. Development of a Selective Estrogen Mimic (SEM) that is effective in breast cancer without uterotrophic and other side effects is a novel treatment option that we hypothesize will be effective in causing regression of tamoxifen-resistant breast cancer. We theorize that a rational approach would be an ER ligand with pharmacological partial agonist actions, thus able to mimic E2 in regressing breast cancer, but with antagonist actions in the face of excessive ER activation. Using the benzothiophene scaffold common to the clinical Selective Estrogen Receptor Modulators (SERMs), raloxifene and arzoxifene, we hypothesized that an ideal SEM could be designed by structural engineering. A library of over 30 compounds was developed and assayed in tamoxifen-resistant cell lines, including MCF-7 and T47D. One SEM was assayed in two mouse xenograft models and shown to cause tumor regression; impressively this SEM did not fuel growth of estrogen-dependent T47D xenografts and did not cause uterine growth. This SEM and several other compounds were observed to act as partial agonists at ERα, with variable actions at ERβ. To understand this phenomenon further, the contributions of apoptotic mechanisms and cell cycle arrest to SEM activity was studied in cell cultures. The results collected to date on SEMs that act as partial agonists at ERα indicate that this is a viable, new approach to breast cancer therapy.

Citation Format: Gregory RJ Thatcher, Rui Xiong, Hitisha K Patel, Jiong Zhao, Xiao Liang, Yue-ting Wang, Mary Ellen Molloy, Debra Tonetti. Novel, non-uterotrophic, selective estrogen mimics cause regression of tamoxifen-resistant breast cancer in 2D and 3D cultures and in mouse xenograft models [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-23.
Abstract P3-05-24: Adaptation to AI therapy in breast cancer can induce dynamic alterations in ER activity resulting in estrogen independent metastatic tumours
Authors: Vareslija Damir , McBryan Jean , Fagan Ailis , Redmond Aisling , Hao Yuan , Hill Arnold DK , Young Leonie S
Published: May 2015

Acquired resistance to aromatase inhibitor therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumour cells develop this resistance remain unclear. Here, discovery of pro-survival adaptations to the estrogen receptor (ER) signalling pathway in response to AI treatment is reported. Global ChIPseq analysis shows that the ER retains binding activity in AI resistant cells under steroid-depleted conditions. In AI treated patients, evidence of steroid independent adaptive ER signalling was demonstrated by the ER target gene Early Growth Response 3 (EGR3). Expression of EGR3 decreased initially upon AI treatment but subsequently recovered following as little as 12 weeks of AI treatment. In vitro data indicates that this increased expression of EGR3 may enhance cell growth and motility of tumour cells. Finally, evidence from established metastatic tumours suggests that the ER signalling network may undergo further adaptations with disease progression as EGR3 expression is routinely lost in the established metastatic tumour. Overall, these data provide evidence of a dynamic ER response to AI treatment which may provide vital clues for overcoming the clinical issue of AI resistance.

Citation Format: Damir Vareslija, Jean McBryan, Ailis Fagan, Aisling Redmond, Yuan Hao, Arnold DK Hill, Leonie S Young. Adaptation to AI therapy in breast cancer can induce dynamic alterations in ER activity resulting in estrogen independent metastatic tumours [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-24.
Abstract P3-07-19: Breast cancer risk perception and adherence to U.S. cancer prevention guidelines
Authors: Hofstatter Erin , Chagpar Anees
Published: May 2015

Introduction: In the United States, nearly 200,000 cancer-related deaths each year are attributed to poor diet and physical inactivity. We sought to determine whether perceived personal breast cancer risk was associated with adherence to healthy lifestyle habits in a nationally representative sample.

Methods: The National Health Interview Survey (NHIS) is a population-based survey conducted each year by the CDC, designed to represent the non-institutionalized civilian population in the United States. We utilized data from the 2010 NHIS adult and cancer supplements to compare fruit/vegetable intake, alcohol use and exercise habits among women who perceived themselves to be at high risk of developing breast cancer versus those women who perceived themselves to be at average or low risk.

Results: In 2010, 12,055 women without a history of cancer were surveyed, representing 94,990,140 people in the population. Perceived risk of breast cancer was not associated with improved adherence to nutrition and physical activity guidelines (see Table). Less than 5% of all U.S. women meet the recommended fruit/vegetable intake regardless of perceived risk, and only one-third of all women achieve recommended physical activity. Approximately 95% of women adhere to guidelines regarding alcohol intake. On multivariate analysis, perceived risk did not affect health habits when controlling for age, ethnicity, education, insurance status, income, region and body mass index (BMI).

Conclusion: Thousands of breast cancer diagnoses and deaths could be prevented each year through healthy diet and exercise. Yet, a striking majority of U.S. women do not adhere to cancer prevention recommendations, including those women who perceive themselves to be at high risk of breast cancer. These findings suggest that patient education and awareness of personal breast cancer risk may be essential, but not sufficient, for motivating meaningful behavior change.

Univariate AnalysisMultivariate AnalysisPerceived High Risk-% meeting guidelinesPerceived Low/Avg Risk-% meeting guidelinesp-valueOR (95% CI)p-valueFruit/Veg Intake (>=5 svg daily)4.90%4.42%0.56791.14 (0.78-1.66)0.5110Alcohol Intake (<=7 svg/wk)94.22%95.13%0.30930.84 (0.61-1.17)0.3076Physical Activity (75-150 min vig-mod act/wk)30.11%27.74%0.14651.02 (0.87-1.21)0.7921

Citation Format: Erin Hofstatter, Anees Chagpar. Breast cancer risk perception and adherence to U.S. cancer prevention guidelines [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-19.
Abstract P3-08-04: Aspirin and breast cancer risk for BRCA1 and BRCA2 mutation carriers
Authors: Kornhauser Naomi , Terry Mary Beth , Vahdat Linda T , Andrulis Irene , Buys Saundra , Daly Mary , John Esther , Hopper John L , Cigler Tessa
Published: May 2015

Background : Although epidemiologic studies have found evidence that aspirin use may be inversely associated with breast cancer (BC) risk, little is known about whether this applies to BRCA1 and BRCA2 mutation carriers.

Methods : We compared aspirin use in 613 women with BRCA1 or BRCA2 mutations from the six centers of the Breast Cancer Family Registry (BCFR) who were recruited at baseline and completed a questionnaire at 10 year follow-up. We defined cases as carriers with BC (n = 215 with BRCA1 mutations and 137 with BRCA2 mutations) and controls as carriers unaffected with BC (n = 141 with BRCA1 mutations and 120 with BRCA2 mutations). We used logistic regression to estimate odds ratios and 95% confidence intervals separately by gene mutation type.

Results : Three cases (1.4%) and 27 controls (19.1%) among the BRCA1 carriers and 3 cases (2.2%) and 25 controls (20.8%) among the BRCA2 carriers reported ever use of aspirin-based medications before diagnosis. Aspirin use before diagnosis was inversely associated with BC risk for both BRCA1 (OR, 0.13; 95% CI, 0.04-0.46 for ever vs. never use) and BRCA2 (OR, 0.12; 95% CI, 0.03-0.41 for ever vs. never use) carriers, after adjusting for age and center for BRCA1 carriers and age for BRCA2 carriers.

Conclusion : If replicated by larger, prospective studies, aspirin use could become an inexpensive and acceptable risk-reducing measure for BRCA1 and BRCA2 mutation carriers.

Citation Format: Naomi Kornhauser, Mary Beth Terry, Linda T Vahdat, Irene Andrulis, Saundra Buys, Mary Daly, Esther John, John L Hopper, Tessa Cigler. Aspirin and breast cancer risk for BRCA1 and BRCA2 mutation carriers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-04.
Abstract P3-11-09: Elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer after neoadjuvant chemotherapy
Authors: Wang Lei , Ni Xiao-Jian , Qian Guo-Wei , Ou-Yang Qian-Wen , Zhang Xiao-Lan , Jiang Yi-Zhou , Chen Sheng , Hu Xin , Shao Zhi-Ming
Published: May 2015

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced breast cancer (LABC). However, the lack of efficient method to predict the treatment response and prognosis limits the clinical evaluation of the patient eligibility. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies and nasopharyngeal carcinoma, but has not been studied in breast cancer. The purpose of this study is to evaluate whether the LMR is a predictor of the curative impact of LABC patients after NAC and short/long-term mortality. A retrospective cohort of 542 LABC patients who received NAC was recruited between May 2002 and August 2011. The counts for peripheral absolute lymphocyte and monocyte before NAC were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate Cox proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS) and disease-free survival (DFS) respectively. Univariate analysis revealed that higher LMR level (≥4.25) was significantly related to better overall response rate (P = 0.005). Univariate analysis revealed that higher LMR level (≥4.25) was significantly associated with superior OS (P = 0.014), DFS (P = 0.009). The higher lymphocyte count (≥1.5×109/L) was significantly associated with better OS (P = 0.035), while the lower monocyte count (<0.4×109/L) was associated with better OS (P = 0.007) and DFS (P = 0.01), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR = 0.636, 95% confidence interval or 95% CI = 0.432-0.937; P = 0.022), DFS (HR = 0.666, 95% CI = 0.495-0.896; P = 0.007) respectively. The traditional predictive factors, including tumor size, lymph node status, hormone receptor status and HER2 status, were also independent prognostic factors of OS and DFS. The elevated pre-NAC peripheral LMR level was a significant favorable factor for NAC LABC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of LABC patients after NAC.

Citation Format: Lei Wang, Xiao-Jian Ni, Guo-Wei Qian, Qian-Wen Ou-Yang, Xiao-Lan Zhang, Yi-Zhou Jiang, Sheng Chen, Xin Hu, Zhi-Ming Shao. Elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-09.
Abstract P3-13-10: The maintenance treatment after xeloda contained regimens with xeloda or endocrine for HR positive and HER2 negative MBC patients
Authors: Jiang Zefei , Qi Fan , Zhang Shaohua , Bian Li , Wang Tao , Li Lei
Published: May 2015

Objective To discuss the optimizing selection of maintenance treatment after xeloda-contained chemotherapy regimen being applicated in HER-2 negative, HR positive relapsing metastatic breast cancer(MBC) patients, and contrast the curative effect of maintenance treatment with xeloda or endocrine. Methods 119 patients with HER-2 negative, HR positive were enrolled during 2009-2013.All patients taking the xeloda contained chemotherapy regimens to obtain CR,PR or SD were randomly divided into group A(65 cases, maintenance capecitabine therapy 800-1000mg/ m2 bid, orally, Days 1 ∼ 14, q3w)and group B(54 cases, a switch to maintenance endocrine therapy). Endpoints include overall survival (OS) and progression-free survival (PFS). Results The ages, menopausal status, number of metastases and treatment line numbers had no statistical differences between two groups, and the p value of two therapy co-operative groups was 0.002. There were 37 patients(56.9%)using TX and 28(43.1%)using NX in therapy co-operative group A. There were 39 patients (72.2%)using TX, 9(16.7%)using NX and 6(6%) using regimen containing xeloda in therapy co-operative group B. Progression-free survival was 8 months in patients who follow by xeloda and 12 months in those who follow by endocrine (p<0.01).Conclusion Endocrine therapy after xeloda-contained chemotherapy regimen tend to be more effective than single xeloda therapy for patients with HER-2 negative, HR positive. This results request to be verified by advanced OS data, which was needed to in-depth study in clinic and explore relevant biological indicators.

Citation Format: Zefei Jiang, Fan Qi, Shaohua Zhang, Li Bian, Tao Wang, Lei Li. The maintenance treatment after xeloda contained regimens with xeloda or endocrine for HR positive and HER2 negative MBC patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-10.
Abstract P4-01-18: The relationship between components of tumour inflammatory cell infiltration and hematogenous metastasis in patients with primary breast cancer
Authors: Wu Naping , Wang Jue , Xia Tiansong , Zhou Wenbin , Liu Zhao , Zhao Yi , Liu Xiaoan , Zha Xiaoming , Wang Shui
Published: May 2015

Background: Tumors are infiltrated by inflammatory cells (e.g. macrophages, B and T lymphocytes), which may promote tumor growth and invasion. However, the clinical correlation between hematogenous metastasis and relative amount of inflammatory cells is still unknown.

Methods: The prevalence of circulating tumor cells (CTC) in peripheral blood of 133 breast cancer patients was detected by a multimarker comprised of cytokeratin 19 (CK19), small breast epithelial mucin (SBEM) and human mammaglobin (hMAM) real time quantitative RT-PCR (QPCR) platform. Meanwhile, CD68+macrophages, CD20+B lymphocytes and CD3+T lymphocytes at the peritumor and intratumor were also counted by immunohistochemical examination, in corresponding primary invasive breast carcinomas. The relationship between CTC in peripheral blood and inflammatory cell infiltration was analyzed.

Results: The positive rate of CTC was 39.8% (53 out of 133). The prevalence of CTC in peripheral blood was only observed in invasive breast carcinomas. There were more inflammatory cells at the peritumor than the tumor center (P < 0.001).In addition, higher total numbers of infiltrating both CD68+macrophages and CD3+T lymphocytes were associated with significantly the prevalence of CTC in peripheral blood (P < 0.05).

Conclusion: Our data support a hypothesis that CD68+macrophage and CD3+T lymphocyte infiltrating in the breast cancer microenvironment may promote tumor cells disseminating through circulation system.

Citation Format: Naping Wu, Jue Wang, Tiansong Xia, Wenbin Zhou, Zhao Liu, Yi Zhao, Xiaoan Liu, Xiaoming Zha, Shui Wang. The relationship between components of tumour inflammatory cell infiltration and hematogenous metastasis in patients with primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-18.
Abstract P4-01-19: The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients
Authors: Jiang Zefei , Zhou Jinmei , Wang Tao , Liu Yi , Li Lei , Zhang Huiqiang , Zhang Shaohua , Bian Li , Song Santai
Published: May 2015

Background: Circulating tumor cell (CTC) and serum HER2 ECD can all reflect an aggressive tumor behavior. We performed this prospective, monocenter, double-blinded study to investigate the potential clinical significance of combined detection of CTC and serum HER2 ECD for advanced breast cancer patients with histological HER2-positivity.

Methods: A total of 88 eligible patients were enrolled in the present study from April 2012 to October 2013. We used Cell search system and ADVIA Centaur System to detect CTC and serum HER2 ECD respectively. Patients received systemic treatment according to national and international guidelines.

Results: Twenty nine (33%) patients had ≥5 CTC, seventy three (83%) patients had serum HER2 ECD values of at least 15ng/ml, twenty seven (30.7%) patients had both elevated CTC and ECD values and fourteen (15.9%) patients had both normal CTC and ECD values. Patients with both normal CTC and serum HER2 ECD values exhibited a significantly longer median PFS than patients with both elevated values (9.0 months versus 2.8 months, p=0.023) and exhibited a trend toward longer PFS compared with patients with elevated CTC or ECD values (9.0 months versus 4.2 months, p=0.065), patients with both or one elevated values showed similar median PFS (2.8 months versus 4.2 months, p=0.211) (Figure1).

Conclusions: The combined detection of CTC and serum HER2 ECD showed prognostic significance for HER-2 positive advanced breast cancer patients, patients with both normal values exhibited longer median PFS than others.

Citation Format: Zefei Jiang, Jinmei Zhou, Tao Wang, Yi Liu, Lei Li, Huiqiang Zhang, Shaohua Zhang, Li Bian, Santai Song. The combined detection of CTC and serum HER2 ECD predict PFS for HER2-positive advanced breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-19.
Abstract P4-04-05: Contributions of STAT3 to pro-tumorigenic alterations within the microenvironment during mammary tumorigenesis
Authors: Chuntova Pavlina , Bohrer Laura R , Schwertfeger Kaylee
Published: May 2015

Interactions between tumor cells and their surrounding microenvironment are critical for the development and progression of breast cancer. Specifically, oncogenic alterations such as aberrant activation of growth factor receptors in epithelial cells lead to a pro-tumorigenic inflammatory response characterized by increased production of inflammatory factors and increased macrophage infiltration. Our studies focus on identifying novel mechanisms through which tumor-derived cytokines act in an autocrine manner to regulate tumor cells and in a paracrine manner to regulate infiltrating inflammatory cells. In recent studies, we have shown that following activation of the fibroblast growth factor receptor 1 (FGFR1) oncogene, mammary epithelial cells produce high levels of interleukin 6 (IL-6) family members. These cytokines activate signal transducer and activator of transcription 3 (STAT3) in both epithelial cells and macrophages. STAT3 is constitutively activated in up to 70% of primary breast tumors, and has been shown to enhance proliferation and angiogenesis as well as aid in immune suppression. Using a novel mouse model of FGFR1-driven tumor growth, we demonstrated that inhibition of STAT3 led to decreased tumor growth. Histological examination revealed high levels of STAT3 activation in both tumor cells and macrophages. Thus, further studies focused on identifying mechanisms through which STAT3 activation in different cellular compartments contributes to mammary tumor growth. Initial studies focused on the consequences of STAT3 activation in epithelial/tumor cells. We found that epithelial cell STAT3 activation resulted in accumulation of the extracellular matrix component hyaluronan, which contributed to epithelial cell proliferation, survival and migration. Meanwhile, STAT3 activation in macrophages led to expression changes within a variety of molecules which are known to enhance tumor cell survival, tumor invasion and regulation of the anti-tumor immune response. Thus, it becomes evident that systemic inhibition of STAT3 function can potentially inhibit tumor growth and progression by acting on both tumor cells and on the surrounding stroma. As STAT3 is being considered as a viable target for breast cancer therapy, understanding the mechanisms through which STAT3 promotes tumor growth and progression will be critical for developing optimal therapeutic strategies.

Citation Format: Pavlina Chuntova, Laura R Bohrer, Kaylee Schwertfeger. Contributions of STAT3 to pro-tumorigenic alterations within the microenvironment during mammary tumorigenesis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-05.
Abstract P4-04-13: Cancer-derived miR-105 promotes tumor invasion and destroys the natural barriers against metastasis
Authors: Wang Shizhen Emily , Zhou Weiying , Fong Miranda Y , Min Yongfen , Lin Pengnian Charles
Published: May 2015

Cancer-secreted miRNAs are emerging mediators of cancer–host crosstalk. In this study, we set out to identify cancer-derived miRNAs that participate in cancer metastasis by adapting the niche cells. We show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In epithelial and endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in non-metastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas intervention of miR-105 in highly metastatic tumors alleviates this effect. By testing clinical specimens from breast cancer patients, we further show that miR-105 can be detected in the circulation at the pre-metastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer. Our results demonstrate for the first time the dual roles of miR-105 in inducing the migratory potential of cancer cells as well as destroying the epithelial and endothelial barriers in the cancer niche by targeting the cellular tight junctions. In breast cancer patients, increased levels of miR-105 in the circulation can be detected at the pre-metastatic stage and predict the occurrence of metastasis. Anti-miR-105 treatment suppresses metastasis and abolishes the systemic effect of tumor-derived miR-105 on niche adaptation. Therefore, these pre-clinical observations strongly suggest clinical applications of miR-105 as a predictive or early-diagnostic blood-borne marker as well as a therapeutic target for breast cancer metastasis.

Citation Format: Shizhen Emily Wang, Weiying Zhou, Miranda Y Fong, Yongfen Min, Pengnian Charles Lin. Cancer-derived miR-105 promotes tumor invasion and destroys the natural barriers against metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-13.
Abstract P4-04-16: Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production
Authors: Bowers Laura W , Brenner Andrew J , Hursting Stephen D , Tekmal Rajeshwar R , deGraffenried Linda A
Published: May 2015

Introduction: Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. Resistance to aromatase inhibitor treatment may be one mechanism mediating this effect, as obese patients have a lower response rate to this class of drugs and higher breast tissue aromatase expression. We hypothesized that obesity-associated circulating factors promote breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production, resulting in an elevation in pre-adipocyte aromatase expression that enhances breast cancer cell estrogen receptor activity and proliferation.

Methods: We utilized an in vitro model of the obese patient’s tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI≥30.0 kg/m2) or normal weight (N; BMI 18.5-24.9 kg/m2) postmenopausal women.

Results: Exposure to OB versus N patient sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. This was coupled with 89% greater pre-adipocyte aromatase expression following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N patient sera, a difference nullified by treatment of the MCF-7 cells with the COX-2 inhibitor celecoxib during CM generation. Previous analysis of the sera revealed significantly higher interleukin 6 (IL-6) concentrations in the OB versus N patient samples. Depletion of IL-6 from the sera resulted in neutralization of the difference between OB and N CM-stimulated aromatase expression. N CM generated with the addition of IL-6 treatment at the time of N patient sera exposure also induced pre-adipocyte aromatase expression that was statistically equivalent to the OB CM condition. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB patient sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N.

Conclusions: This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production, thereby promoting greater cancer cell ERα activity and proliferation. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted.

Citation Format: Laura W Bowers, Andrew J Brenner, Stephen D Hursting, Rajeshwar R Tekmal, Linda A deGraffenried. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-16.
Abstract P4-04-26: Down-regulation of p16INK4a inhibits miR-146b-5p and modulates IL-6 in breast stromal fibroblasts
Authors: Al-Ansari Mysoon M , Aboussekhra Abdelilah
Published: May 2015

Breast cancer is a major health problem that threatens millions of women’s lives each year worldwide. Cancer-associated fibroblasts (CAFs), which constitute the major component of the tumor stroma, have been reported to actively contribute to tumor cells proliferation and invasion. Recently, we have shown down-regulation of the tumor suppressor p16INK4a protein in breast cancer-associated fibroblasts. Moreover, p16INK4a deficiency led to the activation of the stromal fibroblasts, which express/secrete elevated levels of IL-6, a major player in breast carcinogenesis. We have shown here that p16INK4a negatively regulates the IL-6 expression and secretion in breast stromal fibroblasts. Furthermore, we have shown that IL-6 is playing a major role in mediating the paracrine pro-carcinogenic effect of p16-deficient fibroblasts. We have also shown that p16INK4a inhibits the IL-6 expression in a miRNA-146b-5p-dependent manner. Importantly, we present clear evidence that miR-146b-5p inhibition activates breast stromal fibroblast. Indeed, miR-146b-5p inhibition increased the migration/invasion abilities of breast stromal fibroblasts, and the paracrine effect of these cells on the migration/invasion of breast cancer cells. Furthermore, miR-146b-5p-deficient stromal fibroblasts triggered epithelial to mesenchymal transition in breast cancer cells in a paracrine manner. In addition, we have shown that miR-146b-5p is down-regulated in CAFs as compared to their adjacent counterpart fibroblasts. These results indicate that p16INK4a negatively regulates IL-6 through the activation of miR-146b-5p, which plays a major role in repressing breast stromal fibroblasts and inhibiting their pro-carcinogenic effects. This indicates that miR-146b-5p has cell-non-autonomous tumor suppressor function. Therefore, this miRNA could be of great therapeutic value.

Citation Format: Mysoon M Al-Ansari, Abdelilah Aboussekhra. Down-regulation of p16INK4a inhibits miR-146b-5p and modulates IL-6 in breast stromal fibroblasts [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-26.
Abstract P4-04-27: Chemokines released by breast cancer-associated fibroblasts induce epithelial to mesenchymal transition in MCF7 breast cancer cells
Authors: Soon Patsy S , Kim Edward , Benn Diana E , Baxter Robert
Published: May 2015

Purpose: The tumour microenvironment plays a critical role in tumour progression, with cancer-associated fibroblasts (CAFs) in particular being involved in this process (1). Treating breast cancer cells with conditioned media from CAFs has been shown to induce epithelial-mesenchymal transition (EMT) of the breast cancer cells compared to conditioned media from normal breast fibroblasts (NBFs) (2). This study aims to identify factors released by CAFs which induce EMT in breast cancer cells.

Methodology: Primary cultures of six pairs of CAFs and NBFs were established from breast cancer patient samples. Serum-free conditioned media from these cells were collected for chemokine array analysis. MCF7 breast cancer cells were treated with recombinant chemokines and their corresponding receptor antagonists. Vimentin levels, as determined by immunoblot, and cell invasiveness, as measured by transwell assay, were used as indicators of EMT.

Results: Chemokine array showed that CAFs secreted more CXCL1, CXCL8, CXCL12 and CCL2 compared to matched NBFs. Recombinant CXCL8, CXCL12 and CCL2, but not CXCL1, were able to induce vimentin and to increase invasiveness in MCF7 cells. Antagonists for receptors of CXCL8, CXCL12 and CCL2 counteracted the effect of EMT induction on MCF7 cells by recombinant chemokines.

Conclusion: CXCL8, CXCL12 and CCL2, which are secreted at higher levels by CAFs compared to NBFs, induced EMT and increased invasiveness in MCF7 cells. These results suggest that therapeutic targeting of these chemokines or their receptors may be inhibitory to metastasis in some breast cancers.

References:

1. Bhowmick, N A et al. (2004) Nature 432, 332-337

2. Soon, P S et al. (2013) Endocr Relat Cancer 20, 1-12.

Citation Format: Patsy S Soon, Edward Kim, Diana E Benn, Robert Baxter. Chemokines released by breast cancer-associated fibroblasts induce epithelial to mesenchymal transition in MCF7 breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-27.
Abstract P4-05-07: Functional genomics of TP53 mutations and its impact in breast cancer progression
Authors: Pal Anasuya , Gonzalez-Malerva Laura , Eaton Seron , Guzman Mayra , Chow Donald , Yin Hongwei , Park Jin , Anderson Karen , LaBaer Joshua
Published: May 2015

Somatic TP53 mutations are prevalent in basal-like breast cancer (BLBC) tumors. Patients with BLBC tumors have fewer treatment options and respond poorly to current therapies. The majority of TP53 point mutations occurs in the DNA binding domain and can be categorized as either DNA contact or structural mutations. TP53 mutation results in a dominant negative phenotype with neomorphic activity. We predicted that different p53 mutations may lead to different phenotypic characteristics. To investigate this, we generated MCF10A stable transduced cell lines over-expressing the ten most frequent TP53 point mutations associated with breast cancer located in the DNA binding domain of TP53. Ectopic expression of TP53 in these stable cells has been confirmed by qRT-PCR and immunoblot. To assess the impact of mutation on carcinogenesis, we developed a series of high-throughput quantitative assays that measure several hallmarks of cancer, including proliferation, escape from apoptosis, epithelial to mesenchymal transition (EMT), cell migration and invasion, anoikis and morphology in 3D. We observed that one DNA contact mutation with the substitution of a positively charged amino acid with hydrophobic side chains such as R248W, and two structural mutants Y234C and H179R are resistant to apoptosis in presence of doxorubicin, are the most invasive displaying a mesenchymal phenotype characterized by the presence of disrupted B-catenin and E-cadherin staining, with reported worst clinical outcome, suggesting that these are the most aggressive phenotypes. Interestingly, the DNA contact mutants (R248Q, R273H, R248W, and R273C) had a growth advantage in absence of growth factors while structural mutants (R175H, H179R, Y220C, Y234C and Y163C) were more resistant to apoptosis after the cells were challenged with doxorubicin. G245S is comparable to the MCF10Ap53wt and is less proliferative, sensitive to apoptosis, and neither migratory nor invasive. In comparison, R248W which is one of the most aggressive mutants, together with R273C, and H179R resist anoikis; but Y234C, requires matrix for attachment in order to be invasive. In conjunction, these results confirmed our hypothesis that different TP53 point mutants have distinct phenotypes and functional effects on hallmarks of cancer due to distinct underlying cellular programs.

Citation Format: Anasuya Pal, Laura Gonzalez-Malerva, Seron Eaton, Mayra Guzman, Donald Chow, Hongwei Yin, Jin Park, Karen Anderson, Joshua LaBaer. Functional genomics of TP53 mutations and its impact in breast cancer progression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-07.
Abstract P4-05-09: Matrin 3: A novel micro-tubule associated RNA binding protein that acts as a potent tumor suppressor
Authors: Subbarayalu Panneerdoss , Rajamanickam Subapriya , Viswanadhapalli Suryavathi , Dybdal-Hargreaves Nicholas , Timilsina Santosh , Bansal Sanjay , Bansal Hima , Mohammad Tabrez , Chen Yidong , Herr John C , Mooberry Susan L , Rao Manjeet K
Published: May 2015

Microtubules are highly dynamic components of the cytoskeleton that play an important role in a wide range of cellular processes including cell division, cell motility and intracellular transport. Increasing evidence suggests that alterations in microtubule dynamics are critical for cancer growth and metastasis. Microtubule associated proteins (MAPs) regulate microtubule dynamics and consequently can affect sensitivity of cancer cells to microtubule targeting drugs. We discovered a novel microtubule associated protein "Matrin 3 (MATR3)" that is known to bind to RNA and play a critical role in RNA transport and RNA stabilization. Immunofluorescence analyses revealed that although MATR3 is predominantly a nuclear protein, it translocates to the cytoplasm and interacts with microtubules when breast cancer cells are treated with paclitaxel. We show that MATR3 associates with stabilized microtubules and it mediates microtubule polymerization in a taxol-dependent manner. Interestingly, our results reveal that MATR3 acts as a effective tumor suppressor as it inhibits breast cancer colony formation, migration and invasion of breast cancer cells in addition to suppressing breast tumor growth in vivo. Analysis of breast cancer samples showed a significantly lower expression of MATR3 when compared to normal adjacent tissues. Our results indicate the possibility that MATR3 mediates its tumor suppressor function by binding and regulating proteins that are known to affect microtubule dynamics. We believe that nuclear-cytoplasmic shuttling of MATR3 is critical for stability of key proteins that might regulate paclitaxel-dependent microtubule dynamics and subsequently cellular effects in cancer cells.

Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Nicholas Dybdal-Hargreaves, Santosh Timilsina, Sanjay Bansal, Hima Bansal, Tabrez Mohammad, Yidong Chen, John C Herr, Susan L Mooberry, Manjeet K Rao. Matrin 3: A novel micro-tubule associated RNA binding protein that acts as a potent tumor suppressor [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-05-09.