bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-05-04: The histone demethylase hairless functions as a tumor suppressor gene in breast cancer development
Authors: Liu Liang , Shen Yao , Singh Jasvinder , Sah Bindy , Chen Zhongming , Henzler Christine , Ha Wootae , Su Tao , Hibshoosh Hanina
Published: March 2022

The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that HR possesses antitumor activity in skin cancer models. Surveying human cancer genomics datasets identified frequent HR missense mutations or deletions in various human malignancies including breast cancers, suggesting that HR might function as a tumor suppressor in cancer development. By targeted sequencing, we identified HR mutations in approximately 29% of human breast cancer tissues (n=85), compared to 33% for BRCA2 and 17% for BRCA1 in the same sample cohort. Digital PCR assays also revealed frequent HR copy number loss across breast cancer subtypes. To further define HR’s putative tumor suppressor function in breast cancer and its mechanism of action, we reconstituted HR expression in HR-deficient human breast cancer cells. HR re-expression significantly suppressed tumor growth and metastasis in orthotopic xenograft mouse models. This antitumor activity of HR in breast cancer cells was partly associated with transcriptional activation of the CELF2 tumor suppressor gene, a new HR-regulated gene identified by RNA-seq studies. Consistent with HR’s H3K9 demethylase activity, pharmacological inhibition of H3K9 methylation inhibited HR-deficient breast cancer cell proliferation and migration. Taken together, these studies demonstrate that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to reduce HR-deficient breast cancer cell growth and survival. methylation inhibited HR-deficient breast cancer cell proliferation and migration in vitro, and tumor growth and metastasis in xenograft models. Taken together, these studies suggest that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to treat HR-deficient breast cancers.

Citation Format: Liang Liu, Yao Shen, Jasvinder Singh, Bindy Sah, Zhongming Chen, Christine Henzler, Wootae Ha, Tao Su, Hanina Hibshoosh. The histone demethylase hairless functions as a tumor suppressor gene in breast cancer development [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-04.
Abstract P3-09-01: A ubiquitination cascade regulating the integrated stress response and survival in carcinomas
Authors: Cervia Lisa D , Shibue Tsukasa , Gaeta Benjamin , Borah Ashir A , Leung Lisa , Li Naomi , Dumont Nancy , Gonzalez Alfredo , Bick Nolan , Kazachkova Mariya , Dempster Joshua M , Krill-Burger John M , Piccioni Federica , Udeshi Namrata D , Olive Meagan E , Carr Steven A , Root David E , McFarland James M , Vazquez Francisca , Hahn William C
Published: March 2022

Targeting of mutated oncogenes has led to the identification of new targeted therapies. However, druggable oncogenes do not occur in most cancers. Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 793 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitination ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, is required for the survival of a subset of epithelial tumors, particularly subtypes of breast cancer. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization and upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.

Citation Format: Lisa D Cervia, Tsukasa Shibue, Benjamin Gaeta, Ashir A Borah, Lisa Leung, Naomi Li, Nancy Dumont, Alfredo Gonzalez, Nolan Bick, Mariya Kazachkova, Joshua M Dempster, John M Krill-Burger, Federica Piccioni, Namrata D Udeshi, Meagan E Olive, Steven A Carr, David E Root, James M McFarland, Francisca Vazquez, William C Hahn. A ubiquitination cascade regulating the integrated stress response and survival in carcinomas [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-01.
Abstract P3-12-03: Pre-diagnostic plasma 25-hydroxyvitamin D and mortality among women with breast cancer in the nurses’ health study cohorts
Authors: Holder Etienne
Published: March 2022

Background: Sufficient levels of vitamin D are critical for optimal health. 25-hydroxyvitamin D (25(OH)D) is an essential steroid hormone, derived from sun exposure, diet, and supplement use, that is hypothesized to influence breast cancer prognosis by inhibiting breast tumor growth. While this has been observed in laboratory-based studies, findings from observational studies are inconclusive. We examined the association between pre-diagnostic 25(OH)D concentrations and both breast cancer-specific and overall mortality to explore the potential effects of vitamin D, a modifiable exposure. Methods: We evaluated the association between pre-diagnostic plasma 25(OH)D concentrations and breast cancer-specific and total mortality among 1,300 women diagnosed with invasive, non-metastatic breast cancer enrolled in the Nurses’ Health Study 1 (NHS1) and Nurses’ Health Study 2 (NHS2) cohorts. In this analysis, women provided a blood sample from 1989-1990 and a second blood sample in 2000-2001 (NHS1) or a blood sample from 1996-1999 (NHS2). Women were diagnosed with breast cancer after blood collection up through 2016 (NHS1) and 2017 (NHS2) and censored at end of study (2016 NHS1; 2017 NHS2) or death, whichever came first. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for mortality after adjustment for tumor characteristics, type of cancer treatment, and lifestyle factors. For women with two blood samples, most recent exposure status was used in the analyses. Results: A total of 396 total deaths and 145 breast cancer-specific deaths occurred during follow-up through 2017. We observed a non-statistically significant 25% lower breast cancer-specific mortality rate among those with the highest, versus lowest, quartile of pre-diagnostic 25(OH)D levels (HRQ4vsQ1 0.75, 95%CI 0.45-1.25; p for trend=0.32), that did not vary significantly by estrogen receptor status of the tumor (p for interaction=0.61). Women in the highest vs. lowest quartile of plasma 25(OH)D experienced a 31% lower overall mortality rate (HRQ4vsQ1 0.69, 95%CI 0.51-0.93; p for trend=0.03). In cause-specific mortality analyses among non-breast cancer deaths, non-statistically significant decreases were observed for other cancer deaths and cardiovascular disease deaths. Conclusion: Pre-diagnostic plasma 25(OH)D levels were not significantly associated with lower breast cancer-specific mortality among women with breast cancer. However, significant inverse associations were observed for total mortality, which supports a potential benefit of vitamin D among these women.

Citation Format: Etienne Holder. Pre-diagnostic plasma 25-hydroxyvitamin D and mortality among women with breast cancer in the nurses’ health study cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-03.
Abstract P3-12-14: Attenuated negative prognostic effect of progesterone receptor negativity in postmenopausal ER+ breast cancer with normal BMI (<25): A nation-wide study in Korean Breast Cancer Society and the institutional cohort
Authors: Bae Soong June , Hwang Jawon , Lee Janghee , Ji Jung Hwan , Chu Chihhao , Kim Jee Hung , Ahn Sung Gwe , Jeong Joon
Published: March 2022

Purpose Loss of progesterone receptor (PR) expression is a poor prognostic factor in ER+/HER2- breast cancer. A growing body of evidence suggests that PR expression is affected by endogenous estrogen level and modulated by body mass index (BMI). Using Korean Breast Cancer Society Registry (KBCSR) and institutional database, we evaluated survival outcome by PR expression in the postmenopausal groups stratified by BMI. Moreover, we investigated 21-gene recurrence score to assess intrinsic tumor biology. Method Data from the KBCSR for patients diagnosed with invasive breast cancer when aged over 50 years were reviewed, and 33,314 with BMI were included. Of these, we investigated overall survival (OS) of women at age of 60 and older with a median follow-up of 56 months (n=9,492). In the institutional cohort with ER+HER2- breast cancer women at age of 50 and older (n=703), the landmark survival analyses were performed to address the 5-years recurrence-free survival (RFS). In the subset of the institutional cohort, 21-gene recurrence scores were identified in individuals (n=470). Normal weight is defined as BMI less than 25kg/m2. Result Among the postmenopausal women from the KBCSR, the PR- was significantly associated with adverse OS (hazard ratio [HR], 1.39; 95% CI, 1.16-1.67; p<0.001) in high BMI group (≥25) whereas in normal BMI group (<25) did not (HR, 1.07; 95% CI, 0.89-1.29; p=0.498) (interaction p=0.046). In the institutional cohort with ER+/HER2- postmenopausal women (age>50), RFS was superior in the PR+ than in the PR- in the postmenopausal with high BMI (≥25). In contrast, RFS was not separated by PR in the normal BMI group (<25). When we compared the 21-gene recurrence score according to PR, the scores were significantly lower in the PR+ than in the PR- regardless of BMI. Conclusion In ER+/HER2- aged postmenopausal breast cancer women with normal BMI who have low estrogen environment, negative prognostic effect of absence of PR expression is attenuated. Bad tumor biology of PR- cancer is conserved irrespective of BMI. We support the hypothesis that weight control to reduce endogenous estrogen produced by adipose tissue is beneficial for postmenopausal women with ER+ breast cancer.

Citation Format: Soong June Bae, Jawon Hwang, Janghee Lee, Jung Hwan Ji, Chihhao Chu, Jee Hung Kim, Sung Gwe Ahn, Joon Jeong. Attenuated negative prognostic effect of progesterone receptor negativity in postmenopausal ER+ breast cancer with normal BMI (<25): A nation-wide study in Korean Breast Cancer Society and the institutional cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-14.
Abstract P3-12-22: Socioeconomic position and prognosis in premenopausal breast cancer: A population-based cohort study in Denmark
Authors: Hjorth Cathrine , Damkier Per , Ejlertsen Bent , Lash Timothy L , Sørensen Henrik T , Cronin-Fenton Deirdre
Published: March 2022

Background: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality.Methods: Our cohort included all premenopausal women aged 18-55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007-2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate or high), income (low, medium or high), and employment status (employed, unemployed or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs) and used Poisson regression to compute incidence rate ratios and 95% confidence intervals (95% CIs) of recurrence and death. We stratified on ER status/tamoxifen to evaluate interaction.Results: Our cohort included 2,616 women; 286 (CIP: 13%) experienced recurrence and 223 (CIP: 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased risks of recurrence (IRR: 1.45, 95% CI: 1.11-1.89) and mortality (IRR: 1.83, 95% CI: 1.32-2.52). Furthermore, we observed increased mortality in women with low education (IRR: 1.49, 95% CI: 0.95-2.33), low income (IRR: 1.37, 95% CI: 0.83-2.28), unemployment (IRR: 1.61, 95% CI: 0.83-3.13) or health-related work absenteeism (IRR: 1.80, 95% CI: 1.14-2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen.Conclusions: Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence.

Citation Format: Cathrine Hjorth, Per Damkier, Bent Ejlertsen, Timothy L Lash, Henrik T Sørensen, Deirdre Cronin-Fenton. Socioeconomic position and prognosis in premenopausal breast cancer: A population-based cohort study in Denmark [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-22.
Abstract P3-14-03: The DNA damage repair landscape in Black women with breast cancer
Authors: Mazumder Aloran , Jimenez Athena , Ellsworth Rachel E , George Sophia , Freedland Stephen J , Bainbridge Matthew N , Haricharan Svasti
Published: March 2022

Black women have 42% higher mortality rate from estrogen receptor positive (ER+) breast cancer than white women. Molecular mechanisms underlying worse outcome in black women are understudied. Recently, downregulation of specific DNA damage repair (DDR) genes was shown to causally induce resistance to standard care endocrine therapy by dysregulating cell cycle regulation, and to associate with poor outcome in white women with ER+ breast cancer. However, frequency and patterns of DDR dysregulation in Black women with ER+ breast cancer and impact on survival outcomes remains untested. By assessing RNA expression of 104 DDR genes across three tumor, and two normal breast, datasets, here, we map for the first time, global patterns of DDR gene expression regulation specific to Black women, both in tumors and in the normal breast. We identify a specific subset of 8 candidate DDR genes that are dysregulated at the RNA level in tumors from Black women. Of note, a novel DDR regulation signature where genes from the homologous recombination pathway are upregulated and genes from SSBR pathways (mainly base excision repair) are coincidently downregulated is almost uniquely detectable in tumors from Black women (8% incidence relative to 1% in tumors from white women, p=0.01). Moreover, this coincident DDR signature associates with dysregulated cell cycle gene expression (p<0.001). In accordance, patients whose tumors demonstrate this coincident DDR signature also have significantly worse survival outcomes across datasets (hazard ratio of 9.5, p<0.001). Overall, these results constitute the first systematic analysis of differences in DDR gene expression regulation between Black and white women and identify a specific DDR signature associated with poor outcome in tumors from Black women. These results provide new grounds for refining biomarker profiles and improving precision medicine for underserved populations.

Citation Format: Aloran Mazumder, Athena Jimenez, Rachel E Ellsworth, Sophia George, Stephen J Freedland, Matthew N Bainbridge, Svasti Haricharan. The DNA damage repair landscape in Black women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-03.
Abstract P3-14-04: Genetic testing in non-Hispanic Black women with breast cancer treated within an equal-access healthcare system
Authors: Ellsworth Rachel , Vargason Ashlee , Turner Clesson , Shriver Craig
Published: March 2022

Purpose: Identification of women with hereditary forms of cancer allows for use of precision medicine approaches to improve survival. Non-Hispanic Black (NHB) women in the US general population are less likely to undergo genetic testing or utilize risk-reducing strategies. Whether these disparities exist within the equal-access military healthcare system of the Department of Defense is not known. Methods: Genetic test information and surgical procedures were extracted for all NHB and Non-Hispanic Whites (NHW) with invasive breast cancer who were diagnosed and treated at the Murtha Cancer Center at Walter Reed National Military Medical Center and enrolled in the Clinical Breast Care Project. National Comprehensive Cancer Network criteria from the year of diagnosis were assessed for all patients. Data were analyzed using chi-square analysis with p<0.05 defining significance. Results: NHB were significantly (p=0.009) more likely to meet criteria for genetic testing compared to NHW, however, test uptake did not differ significantly between populations (p=0.292). Pathogenic variant frequency (p=0.597), prophylactic mastectomy (p=0.915) and oophorectomy (p=0.076) did not differ significantly between populations. Conclusion: These data demonstrate that when barriers, such as cost and lack of insurance barriers were removed, NHB were as willing to pursue testing and risk-reducing strategies as their NHW counterparts. Increasing the availability of testing and clinical management for NHB with hereditary forms of cancer may help reduce disparate survival seen in the US general population. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Citation Format: Rachel Ellsworth, Ashlee Vargason, Clesson Turner, Craig Shriver. Genetic testing in non-Hispanic Black women with breast cancer treated within an equal-access healthcare system [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-04.
Abstract P3-14-08: The influence of metabolic factors, migration, and ethnic disparities on breast cancer risk and treatment
Authors: Lofterød Trygve , Frydenberg Hanne , Veierød Marit , Jenum Anne Karen , Reitan Jon B , Wist Erik , Thune Inger
Published: March 2022

Background: Migrant studies have shown an increase in breast cancer incidence rates among immigrants moving from a breast cancer low-incidence to a high-incidence country. However, 30 years after immigration, it remains equivocal to what degree metabolic factors and ethnic disparities affect breast cancer development and treatment. Methods: Using Cox regression models, we examined the association between ethnicity and breast cancer development, and whether this association varied by pre-diagnostic metabolic profiles among 13 802 women, aged 20-75 years, participating in the population-based Oslo Ethnic Breast Cancer Study. Ethnicity was categorized into: women of Western European descent (reference population) and women of non-western ethnicity (ethnic minority). The ethnic minority women were further subclassified into three groups: 1) South Asian, 2) Middle East and North African, and 3) all other non-western origin women. We defined four pre-diagnostic unfavorable metabolic factors (above median body mass index (>24.6 kg/m2), waist:hip ratio (>0.79), triglyceride:HDL-cholesterol ratio (>0.73), and blood pressure (>96.5 mmHg)), which were combined to define three metabolic profiles: (0-2, 3, and 4 unfavorable metabolic factors). A total of 557 women developed invasive breast cancer during a mean 16.5 years of follow-up. Detailed medical records were obtained. Results: Among women with an unfavorable metabolic profile, South Asian women, compared with Western European women, had a 2.3 times higher breast cancer risk (HR 2.30, 95% CI 1.18-4.49). Furthermore, the ethnic minority women, compared with the Western European women, were suggestively more likely to present with triple-negative breast cancer (OR 2.11, 95% CI 0.97-4.61), and less likely to complete all courses of planned taxane treatment (OR 0.26, 95% CI 0.08-0.82). No differences by ethnicity were observed in physicians’ decisions of planned breast cancer treatment, Conclusions: Our results support that metabolic factors, including body composition, serum lipids and blood pressure, are important when balancing breast cancer prevention and disease management among non-western women migrating from a breast cancer low-incidence to a high-incidence country. However, larger studies are needed.

Citation Format: Trygve Lofterød, Hanne Frydenberg, Marit Veierød, Anne Karen Jenum, Jon B Reitan, Erik Wist, Inger Thune. The influence of metabolic factors, migration, and ethnic disparities on breast cancer risk and treatment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-08.
Abstract P3-19-28: The impact of PM2.5 on the radiation-induced pneumonitis in patients with breast cancer
Authors: Kim Dong-Yun , Kim In Ah , Jang Bum-Sup
Published: March 2022

Purpose: Exposure to particulate matter (PM) air pollution has been associated with adverse effect on respiratory disease, but no study has investigated its impact on radiation-induced pneumonitis (RIP) in patients with breast cancer who received adjuvant radiation therapy (RT). Materials and Methods: We conducted a retrospective review of 2,762 breast cancer patients who received postoperative RT between 2017 and 2020 in a single institution. Particulate matter data including PM2.5 and PM10 were retrieved from the open dataset in the ‘Gyeonggi Data Dream’. We used the average, median and maximum values of the PM2.5 and PM10 measured during daytime when a patient visited to the hospital for RT. We excluded the patients when missing PM data exceeded 50% of the total treatment period (N=26). Finally, altogether 2,736 patients were analyzed. Results: Overall incidence rate of RIP was 1.74%. There were no significant differences in average value of PM2.5 and number of RT fractions between RIP (+) and RIP (-) groups, but marginal differences were found in RT techniques (3-dimentional conformal RT vs. intensity modulated RT, P=0.053) and proportion of PM2.5 value ≥ 35 (μg/m3) (P=0.053) between the two groups. After adjusting for age, RT technique, regional irradiation, fractionation and boost, the average value of PM2.5 was significantly associated with a higher risk of RIP (Odds ratio [OR] 1.05, 95% confidential incidence [CI] 1.00-1.10, P=0.047) when patients received ≥ 20 fractions of RT. Especially, PM2.5 ≥ 35 (μg/m3) showed significant higher risk of RIP (OR 4.32, 95% CI 1.34-13.87, P=0.014) in patients with ≥ 20 fractions of RT after adjustment of aforementioned covariates. Other PM data (median, maximum value of PM2.5 and all PM10 values) were not related to the RIP regardless of the number of RT fractions. Conclusion: This is the first study to reveal the association between PM2.5 and RIP in breast cancer patients who received 20 fractions or more of postoperative RT.

Citation Format: Dong-Yun Kim, In Ah Kim, Bum-Sup Jang. The impact of PM2.5 on the radiation-induced pneumonitis in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-28.
Abstract P4-01-09: The WAVE3 phosphorylation/β-catenin oncogenic signaling axis promotes chemoresistance and cancer stemness in triple negative breast cancer
Authors: Wang Wei , Rana Priyanka , Alkrekshi Akram , Markovic Vesna , Sossey-Alaoui Khalid
Published: March 2022

Acquisition of the metastatic phenotype is responsible for the death of ~90% of breast cancer (BC) patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the United States, annually accounting for more than 40,100 deaths and 266,000 new cases of invasive BC. Amongst individual BC subtypes, those classified as TNBCs are especially lethal due to their highly metastatic behavior and propensity to recur rapidly. As a group, TNBCs lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2, which has prevented the development of FDA-approved targeted drug therapies that are effective against this BC subtype. Likewise, recurrent TNBCs frequently acquire resistance to standard-of-care chemotherapeutic agents (e.g., doxorubicin, cyclophosphamides, and taxanes) through mechanisms that remain incompletely understood. We established Wiskott-Aldrich Syndrome Protein-3 (WAVE3) as a novel promoter of TNBC development and metastatic progression. Our recently published studies have shown that WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways. In this study, we show that WAVE3 phosphorylation promotes chemotherapy-resistance and cancer stemness in TNBC, both in vitro and in in vivo mouse models. CRISPR/Cas9-mediated inactivation of WAVE3 resulted in inhibition of 2D growth and 3D tumorspheres’ invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 or the pharmacologic inhibition of WAVE3 phosphorylation did not. Further studies revealed that dual blocking WAVE3 expression or phosphorylation with chemotherapy treatment inhibited the activity and expression of β-catenin. Importantly, a combination of WAVE3-deficiency and chemotherapy suppressed the oncogenic behavior of chemo-resistant TNBC cells, both in vitro and in vivo. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.

Citation Format: Wei Wang, Priyanka Rana, Akram Alkrekshi, Vesna Markovic, Khalid Sossey-Alaoui. The WAVE3 phosphorylation/β-catenin oncogenic signaling axis promotes chemoresistance and cancer stemness in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-09.
Abstract P4-02-07: Lasofoxifene as a potential treatment for aromatase inhibitor resistant ER positive breast cancer
Authors: Laine Muriel , Greene Marianne E , Leng Tiffany , Kurleto Justyna D , Li Sophia , Komm Barry , Greene Geoffrey L
Published: March 2022

Postmenopausal patients with estrogen receptor positive (ERα+) primary invasive breast cancer are typically treated with aromatase inhibitors (AIs) as first line adjuvant therapy. Patients who become resistant to AIs are treated with fulvestrant and/or CDK4/6 inhibitors, such as palbociclib, as second line therapy. Lasofoxifene, a selective estrogen receptor modulator (SERM), was developed for the treatment of vaginal atrophy and osteoporosis. Our previous studies, performed in an MCF-7 xenograph metastatic breast cancer mouse model with activating ERα mutations, showed that lasofoxifene, both alone and in combination with palbociclib, was more effective than fulvestrant at inhibiting tumor growth and metastasis to the liver, lung, bone and brain. In the current study, we compared the efficacy of lasofoxifene +/- palbociclib to fulvestrant +/- palbociclib combinations in a letrozole-induced, AI-resistant breast tumor model (MCF-7 LTLT cells) that does not express ERα activating mutations. Luciferase-GFP tagged LTLT cells were injected into the mammary ducts of NSG mice (MIND model) and tumor progression was monitored by live luminescence imaging of primary tumors, as well as ex vivo imaging and histochemical analysis of metastatic sites at study endpoint. Primary tumor area was also measured at study endpoint. Lasofoxifene +/- palbociclib was significantly more effective than fulvestrant +/- palbociclib at inhibiting primary tumor growth. In addition, all treatments, except fulvestrant, inhibited bone metastasis versus vehicle. These data show that lasofoxifene is more effective than fulvestrant in this tumor model and suggest that lasofoxifene has potential as an effective therapy for AI resistant breast cancers that do not express ERα activating mutations.

Citation Format: Muriel Laine, Marianne E Greene, Tiffany Leng, Justyna D Kurleto, Sophia Li, Barry Komm, Geoffrey L Greene. Lasofoxifene as a potential treatment for aromatase inhibitor resistant ER positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-07.
Abstract P4-04-02: A clinical-stage toll-like receptor 5 agonist, entolimod, boosts chemo-immunotherapy in pre-clinical TNBC by generating durable antitumor immunity
Authors: Brackett Craig M , Aldrich Alyssa R , Greene Kellee F , Kandar Bojidar , Veith Jean , Burdelya Lyudmila G , Abrams Scott I. , Gudkov Andrei V
Published: March 2022

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses, is the most aggressive form of the disease, and has the poorest clinical outcomes. Effective or durable therapies are lacking because these tumors lack targets for therapeutic intervention and rapidly develop resistance to chemotherapy (CTx). The FDA has now approved chemo-immunotherapy (CTx-I) regimens (αPD-L1/nab-Paclitaxel, αPD-1/CTx) as standard-of-care for early-stage, locally advanced, and metastatic TNBC. Despite these advancements, overall response rates remain relatively low and survival outcomes are extended for only a few months especially in the case of locally advanced or metastatic disease. Thus, the need exists to develop additional or alternative strategies to potentially build upon and improve CTx-I protocols for TNBC. To this end, our laboratory has explored the importance of engaging the innate immune response to augment the efficacy of CTx-I. Previously, we demonstrated that toll-like receptor (TLR) 5 signaling can elicit antitumor immunity against a preclinical model of metastatic TNBC. In particular, systemic administration of the TLR5 agonist, entolimod, stimulated durable CD8+ T cell immunity against 4T1, the prototypical preclinical PD-L1+ metastatic TNBC model. Here, using primary 4T1 tumors to mirror the clinical setting of locally advanced disease, we show that entolimod boosts the efficacy of CTx-I (αPD-L1/Paclitaxel) by causing tumor regression. Moreover, these mice completely reject a subsequent tumor challenge, highlighting that the entolimod/αPD-L1/Paclitaxel combination generates durable antitumor immunity in such advanced preclinical settings. Importantly, systemically administered entolimod was shown to be safe in Phase I clinical trials cumulatively involving nearly 200 subjects in both healthy volunteers and advanced cancer patients. Thus, this work will aid in formulating a more effective CTx-I treatment regimen with potentially important clinical implications for patients with locally advanced or metastatic TNBC.

Citation Format: Craig M Brackett, Alyssa R Aldrich, Kellee F Greene, Bojidar Kandar, Jean Veith, Lyudmila G Burdelya, Scott I. Abrams, Andrei V Gudkov. A clinical-stage toll-like receptor 5 agonist, entolimod, boosts chemo-immunotherapy in pre-clinical TNBC by generating durable antitumor immunity [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-02.
Abstract P4-04-12: Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells
Authors: Charan Manish , Das Subhadip , Mishra Sanjay , Varikuti Sanjay , Satoskar Abhay R , Ganju Ramesh K
Published: March 2022

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and lacks the expression of estrogen, progesterone, and Her2 receptors. TNBC is a highly aggressive subtype of breast cancer that has been associated with poorer prognosis and worse overall survival rate. Macrophage migration inhibitory factor (MIF) is a multipotent pro-inflammatory cytokine, highly expressed in various cancers and reported to enhance tumor growth and metastasis. However, its role in influencing the anti-tumor immunity is unexplored. We have previously shown that MIF promotes TNBC growth and metastasis. In addition, CPSI-1306 (MIF inhibitor), reduces its oncogenic effects. Here, we have shown that MIF downregulation in human TNBC xenografts correlate with reduced infiltration of myeloid derived suppressor cells (MDSCs). Furthermore, using a MIF knockout mouse model, we detected reduced MDSC population in the tumor microenvironment. In addition, we observed higher recruitment and increased proliferation of CD3+ T cells. Furthermore, we utilized a syngeneic mouse model to study the effect of MIF inhibition on infiltration of different immune cells in-vivo. CPSI-1306 treatment decreased the recruitment of MDSCs in both the tumor and spleen. In addition, CPSI-1306 treatment promotes the infiltration of CD8+ T cells in both the tumor and spleen. However, CPSI-1306 treatment did not influence the recruitment of CD4+ T cells. We further analyzed the expression of various cytokines and chemokines in blood sera of control and CPSI-1306 treated mice groups using a cytokine array kit. We observed that CPSI-1306 treatment group showed reduced levels of GCSF, GMCSF, IL-2 and IL-4 levels compared to vehicle control groups. Overall, our data strongly suggests that small molecular weight MIF inhibitors could be a potential strategy against TNBC.

Citation Format: Manish Charan, Subhadip Das, Sanjay Mishra, Sanjay Varikuti, Abhay R Satoskar, Ramesh K Ganju. Macrophage migration inhibitory factor regulates triple-negative breast cancer progression by enhancing the recruitment of immune suppressive cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-12.
Abstract P4-04-13: S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages
Authors: Verma Ajeet K , Wilkie Tasha , Mishra Sanjay , Charan Manish , Ganju Ramesh K
Published: March 2022

S100A7 has been shown to be associated with breast cancer growth and metastasis. However, the molecular mechanism through which S100A7 promotes breast tumorigenesis is not completely understood. In this study, we revealed that S100A7 enhanced Stat3-mediated secretion of Serpin-E1 in triple negative breast cancer (TNBC) cell lines. Serpin-E1 has been shown to promote recruitment and polarization toward a pro-tumorigenic phenotype of tumor-associated macrophages through activating the Stat3 pathway. Importantly, we reported that the inhibition of Stat3 led to reduction of S100A7-mediated invasiness of TNBC cells and also significantly decreased the secretion of Serpin-E1 by cancer cells. We also revealed that Stat3 inhibition in TNBC cells or Serpin-E1 neutralization significantly reduced the migration of human monocytes/macrophages by transwell migration assay. We further demonstrate that murine ortholog of S100A7, mS100a7a15 enhanced mammary hyperplasia, tumor growth and metastasis through Stat3 activation. Previously, we reported that S100A7 mediated its tumorigenic effects through RAGE in breast cancer cells. Therefore, we also discovered that combinatorial treatment of Stat3 and RAGE inhibitors in mammary tumor bearing mS100a7a15 overexpression mouse model strongly decreased the tumor burden and enhanced the recruitment of tumor-suppressing M1-macrophages. We also found that combined inhibition of RAGE and Stat3 significantly increased the infiltration of CD4 T cells in the tumor microenvironment (TME). Collectively, these findings suggest S100A7/RAGE signaling pathway could be used as a novel therapeutic target to inhibit breast cancer growth and metastasis through modulating the TME.

Citation Format: Ajeet K Verma, Tasha Wilkie, Sanjay Mishra, Manish Charan, Ramesh K Ganju. S100a7/rage signaling promotes breast tumorigenesis through modulating tumor-associated macrophages [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-13.
Abstract P4-10-11: Eyebrow/eyelash loss among survivors
Authors: Cathcart-Rake Elizabeth , Loprinzi Charles L , Couch Fergus , Olson Janet , Dulmage Brittany , Lustberg Maryam , Larson Nicole , Ruddy Kathryn J
Published: March 2022

Background: Eyebrow and eyelash loss are widely recognized as consequences of some chemotherapies, but prevalence and predictors are understudied. The purpose of this study was to evaluate real world experiences of eyebrow and eyelash loss during treatment for breast cancer. Methods: Breast cancer survivors participating in the ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) were mailed a survey one year after diagnosis. Respondents were asked to recall their severity of eyebrow and eyelash loss since diagnosis, measured from “no loss” to “a little loss” to “a lot of loss” to “complete loss”. Results: 524 participants were mailed a survey including these questions between May 2020 and November 2020; the median time from diagnosis to survey completion was 12 months (range 6 months). Of the 265 participants whose responses were available for analysis (median age 60.8 years), 88 (33%) had received chemotherapy, including 39 (44%) who received doxorubicin and cyclophosphamide, 16 (18%) who received docetaxel and cyclophosphamide, 56 (64%) who received paclitaxel, and 11 (13%) who received carboplatin. 173 (65%) had received endocrine therapy: 56 (32%) of patients who received endocrine therapy received tamoxifen, and 115 (66%) received aromatase inhibitors. 124 (47%) reported at least a little eyebrow loss, and 22 (8%) reported complete loss. Forty-seven percent reported at least a little eyelash loss, and 27 (10%) reported complete loss (Table 1). In the subgroup of 88 patients who received chemotherapy, the rates of at least a little eyebrow and eyelash loss were 50% and 55%, respectively, and rates of complete loss were 8% and 9%. Rates of eyebrow and eyelash loss did not appear to differ significantly by age. Conclusion: Eyebrow and eyelash loss are frequently reported during breast cancer-directed therapy. Future investigations into the incidence and treatment of this side effect are needed.

Table 1.<55 years old55+ years oldEyebrow Loss (N)%Eyelash Loss (N)%Eyebrow Loss (N)%Eyelash Loss (N)%No Loss4551%4753%9655%9353%A Little Loss2629%2225%3922%3922%A lot of loss1011%1112%2715%2514%Complete Loss89%910%148%1810%Funding Source: Breast Cancer Research Foundation (CLL) Clinic

Citation Format: Elizabeth Cathcart-Rake, Charles L Loprinzi, Fergus Couch, Janet Olson, Brittany Dulmage, Maryam Lustberg, Nicole Larson, Kathryn J Ruddy. Eyebrow/eyelash loss among survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-11.
Abstract P4-10-13: Area deprivation index and rurality in relation to financial toxicity among breast cancer surgical patients - Investigating geospatial differences in risk profiles
Authors: Corkum Joseph P , Zhu Victor , Agbafe Victor , Chu Carrie , Colen Jessica Suarez , Greenup Rachel , Offodile Anaeze C.
Published: March 2022

Background: Financial toxicity (FT) depicts the burden of cancer treatment-costs and is associated with lower quality-of-life and survival in breast cancer survivors. We examined the relationship between geospatial location, represented by rurality and Area Deprivation Index (ADI), and risk of FT.Study Design: A single-institution, cross-sectional study was performed on adult female surgical breast cancer patients. Chart reviews were used to obtain patient information while FT was identified using a validated instrument. Patients’ home addresses were used to determine rurality using the Rural Urban Continuum Codes and linked to national ADI score. Tertile ADI groups enabled statistical analysis and multivariate logistic regression models were developed to determine the independent effects of geospatial location and FT.Results: A total of 568 surgical breast cancer patients were included. Univariate analyses showed significant differences across ADI tertiles with respect to race/ethnicity, marital status, insurance type, education, and rurality. Following multivariate analysis, advanced cancer stage (OR 2.26, CI: 1.15-4.44), and escalating ADI (OR 1.012, CI:1.005-1.020) were associated with worsening FT. Increasing age (OR 0.976, CI: 0.96- 0.992), marital status (OR 0.458, CI: 0.299-0.699), receipt of bilateral mastectomy (OR 0.558, CI: 0.323-0.964) were protective of FT. Increasing ADI was also significantly associated with use of coping strategiesConclusion: FT was significantly associated with areas of higher socioeconomic deprivation as measured by the ADI. However, rurality was not found to be a significant predictor of FT. ADI may be used to facilitate pre-operative screening of at-risk populations and the deployment of community-based interventions to alleviate FT.

Multivariate logistic regression analysis results.

Citation Format: Joseph P Corkum, Victor Zhu, Victor Agbafe, Carrie Chu, Jessica Suarez Colen, Rachel Greenup, Anaeze C. Offodile. Area deprivation index and rurality in relation to financial toxicity among breast cancer surgical patients - Investigating geospatial differences in risk profiles [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-13.
Abstract P4-11-21: Plasma cytokine levels in breast cancer-related lymphedema patients
Authors: Vang Anna R , Shaitelman Simona F , Sevick-Muraca Eva M , Wen-yaw Chan , Rasmussen John C , DeSnyder Sarah D , Aldrich Melissa B
Published: March 2022

Background: Breast cancer-related lymphedema (BCRL) is encountered by approximately 40% of breast cancer survivors. BCRL drastically affects quality of life, as the arm, breast, and trunk swelling, together with pain, depression, and cellulitis risk can make everyday functions difficult or impossible. Objective: To identify plasma biomarkers that can suggest targeted pharmacological treatments for breast cancer survivors who develop lymphedema (LE). Methods: In a prospective, ongoing, longitudinal clinical study (NCT02949726), peripheral blood, perometric arm volumes, and near-infrared fluorescence lymphatic images/videos (NIRF-LI) for the first 33 enrolled advanced breast cancer patients were collected pre-mastectomy/breast-conserving surgery with ALND, four weeks postoperatively, at the end of radiation therapy (RT), and at 6 months post-RT. 29 cytokines were measured at each time point using a MILLIPLEX MAP human cytokine/chemokine magnetic bead panel from isolated blood plasma. Cytokine levels in subjects with >5% perometric arm swelling at 6 months post-regional nodal RT were analyzed and compared to those with <5% perometric arm swelling at 6 months post-regional nodal RT. Additionally, subjects who exhibited LE-associated dermal backflow, identified by cloudy fluid masses, instead of linear vessels, with NIRF-LI, at 6 months post-regional nodal RT were compared to those without backflow at 6 months post-regional nodal RT. GraphPad/Prism 9 non-parametric Mann-Whitney t-test was used to compute the p-values of each cytokine. P-values less than 0.05 were deemed significant. Results: Out of the 33 subjects, 7 developed >5% perometric arm swelling 6 months post-regional nodal RT and 15 developed dermal backflow 6 months post-regional nodal RT. Of the 15 subjects that developed backflow, 7 also had >5% perometric arm swelling. G-CSF, GM-CSF, IL-10, IL-12p40, and IL-1R-alpha were found to be significantly higher in subjects with >5% perometric arm swelling at 6 months post-RT than in subjects with <5% perometric arm swelling while IL-1beta was identified to be significantly lower in subjects with backflow at 6 months post-regional nodal RT than those without backflow at 6 months post-regional nodal RT. Conclusions: G-CSF, GM-CSF, IL-10, IL-12p40, IL-1Ralpha, and IL-1beta are candidate biomarkers for detecting and directing pharmacological treatment for lymphedema in breast cancer survivors.

Citation Format: Anna R Vang, Simona F Shaitelman, Eva M Sevick-Muraca, Chan Wen-yaw, John C Rasmussen, Sarah D DeSnyder, Melissa B Aldrich. Plasma cytokine levels in breast cancer-related lymphedema patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-21.