The role of LINE retroelements in breast cancer development

e18500 Background: Approximately 1.4 million adult Americans identify as transgender (TG) or non-binary (NB), a number that has steadily increased over time. In this population, cancer risk is unclear, and screening and treatment guidelines are lacking. We sought to assess TG and NB persons’ perceptions towards breast and cervical cancer screening, risk of cancer development, and thoughts towards gender-affirming hormone therapy in the setting of a hormone-receptor positive breast cancer. Methods: A single-institution online survey was administered from October 2021-January 2022 at our comprehensive LGBTQ+ Inclusion Health Clinic. Participants with female sex at birth were asked about breast and cervical cancer, while those assigned male sex at birth were exclusively asked about breast cancer. A 5-point Likert scale was used to assess attitudes toward cancer screening and concerns regarding cancer development. Results: 40 patient responses were collected: 13% were TG women, 45% TG men, 23% NB, and 20% identified as other (i.e., agender, genderqueer, etc). 71% were assigned female sex at birth (59% of whom had chest masculinization surgery), 27% were assigned male sex at birth, and one individual was intersex at birth. 52.5% were age < 30, 84% were Caucasian, 65% had at least a bachelor’s degree, and all but one respondent had health insurance. The majority reported they were not familiar with breast (77%) or cervical (60%) cancer screening recommendations for their sex-assigned at birth or current gender identity. 23% reported concern regarding breast cancer development and cited family history as the primary reason. In patients age > 40, 50% had a mammogram (MMG) in the past 10 years. When presented with information regarding screening MMG and automated breast ultrasonography (ABUS), 78% reported they would prefer ABUS over MMG for breast cancer screening. 84% of respondents were currently using or had previously used gender-affirming hormone therapy, and of these, 61% reported they would stop therapy in the event they developed a hormone-receptor positive breast cancer. In patients assigned female sex at birth, 25% had a hysterectomy and, in those who still had a cervix, 50% reported having a Pap smear in the past 5 years and 38% were concerned about cervical cancer development. Conclusions: This survey identified that > 60% of TG and NB individuals are unaware of breast and cervical cancer screening guidelines, > 20% are concerned about breast and cervical cancer development, and < 50% of patients eligible for breast and cervical cancer screening had undergone screening in recent years. Additionally, in the setting of a hormone-receptor positive breast cancer, only 61% would consider stopping gender-affirming hormone therapy. Further data on the risk of breast and cervical cancer development and incidence in TG and NB persons is needed to inform optimal screening and treatment guidelines.

Goals: Ion transporters play an important regulatory role in the progression and development of breast cancer (BC). Slc26a9 is a member of the Slc26a anion transporter family, which is mainly involved in regulating the secretion of chloride ions and bicarbonate, but the role of Slc26a9 in HER2-positive BC is still unclear. Methods: Tissue microarray and BC cell line were used to detect the expression level of Slc26a9 and its clinical relevance. By changing the expression level of Slc26a9 gene in BC cells, the effect of Slc26a9 gene on the biological behavior of BC cells and its related molecular mechanism were discussed. Results: We found that the expression of Slc26a9 was significantly upregulated in BC compared with adjacent tissues, and the upregulated Slc26a9 was associated with TNM staging and poor prognosis in BC patients. In addition, the expression of Slc26a9 was significantly upregulated in HER2-positive BC compared with HER2-negative BC, and similar results were obtained in BC cell lines, with Slc26a9 was the highest expression in HER2-enriched SKBR3 cells. Functionally, the proliferation, migration, invasion and anti-apoptotic abilities of SKBR3 cells were significantly inhibited after silencing Slc26a9, and tumorigenesis and metastasis were significantly inhibited in vivo. On the contrary, overexpression of Slc26a9 resulted in the opposite result. Mechanistically, overexpression of Slc26a9 activated the PI3K/AKT/mTOR signaling pathway, the key signaling pathway implicated in HER2-positive breast carcinogenesis, and promoted the expression of downstream proliferation related genes CCND1 (Cyclin D1) and c-Myc, and downregulated the expression of apoptosis related genes Caspase9, apoptosis-inducing factor (AIF) and endonuclease G (Endo G), indicating the simultaneous inhibition of caspase dependent and independent apoptosis pathway. At the same time, accompanied by changes in markers of epithelial-mesenchymal transition (EMT), including downregulation of E-cadherin and ZO-1, and upregulation of N-cadherin and Fibronectin, and SKBR3 cells changed from epithelioid morphology to mesenchymal morphology. In addition, immunofluorescence and protein nucleoplasm separation experiments showed that Slc26a9 upregulated the expression of HER2 and co-localized with HER2 in the nucleus. Co-immunoprecipitation experiments proved that Slc26a9 interacted with HER2. Furthermore, trastuzumab downregulated the expression of Slc26a9 by targeting HER2 in SKBR3 cells. Moreover, when Slc26a9 was overexpressed, the inhibitory effect of trastuzumab on HER2 was partially reversed, and we also verified the PI3K/AKT/mTOR signaling pathway. Not only that, we found that Slc26a9 was significantly upregulated in drug-resistant cell lines relative to parental cells by constructing SKBR3 drug-resistant cell lines, indicating that Slc26a9 expression was significantly correlated with chemotherapy resistance in HER2-positive BC. Conclusion(s): Slc26a9 may interact with HER2 in the form of molecular chaperones to activate PI3K/AKT/mTOR signaling pathway to promote the progression and development of HER2-positive BC and be associated with chemotherapy resistance, but the precise molecular mechanism needs further exploration. Conflict of Interest: No significant relationships. Citation Format: Zhengxing Zhou, Zhiyuan Ma, Xuemei Liu, Chengmin Zhang, Hu Wang, Renmin Mu, Xiaoming Cheng, Biguang Tuo, Taolang Li. Slc26a9 cooperates with HER2 to regulate the progression and development of HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-19.

Studies of the etiology, early detection, and prevention of breast cancer reported in the past year are reviewed in this paper. Studies of the etiology of breast cancer include reports on genetic and environmental factors. A major advance in the study of inherited forms of breast and ovarian cancer occurred with the identification of the BRCA1 gene. A second breast cancer susceptibility gene, the BRCA2 gene, was localized to chromosome 13q12-13. Multiple mutations in the BRCA1 gene have been identified, presenting a challenge for the development of predictive testing. Controversy continues over the association between hormone replacement therapy and the development of breast cancer. A study of exercise suggests a strong protective effect against the development of early onset breast cancer. Recent studies have failed to find a strong link between dietary fat intake and the development of breast cancer. A meta-analysis of studies of the efficacy of screening for the prevention of breast cancer mortality demonstrates a significant reduction in mortality among women 50 years of age and older. A lowering of breast cancer mortality for women aged 40 to 49 was only demonstrated after 10 to 12 years of follow-up. The risks and benefits of tamoxifen therapy, a potential breast cancer chemoprevention agent, continue to be clarified. Adverse effects on the endometrium, including an increased risk of endometrial cancer, have been reported. Beneficial effects include an improved cardiovascular risk profile and preservation of bone mineral density among postmenopausal women.

TP53 is the most frequently mutated gene in human breast cancers and its mutations have been found in all breast cancer subtypes (e.g., luminal, basal-like, claudin-low). Genome-sequencing studies predict that TP53 mutation is an early event in breast cancer development. However, how p53-deficiency contributes to breast cancer initiation, leading to development of different subtypes of breast cancer, remains largely elusive. To address this, we developed a novel approach to trace development of breast cancer from luminal mammary epithelial cells (MECs), which may represent cells of origin for most breast cancers. Our approach is based on induced loss of p53 in luminal MECs at the level of single cells, via intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 promoter (Ad-K8-Cre). This genetic approach permits evolution of single mutant luminal MECs in their native habitat through interaction with the microenvironment (e.g., neighboring p53-wild type MECs, stromal cells, immune cells), and allows us to dissect contributions from genetic, epigenetic, and environmental factors to breast tumorigenesis. Lineage and clonal analyses revealed that induced loss of p53 alone in luminal MECs triggered their clonal expansion without affecting their original luminal identity, leading to formation of a p53-deficient luminal premalignant field. Molecular analysis of luminal MECs in this premalignant field revealed potential involvement of environmental factors (e.g., cyclic ovarian hormones, immune cells in the mammary gland microenvironment) in its formation. Claudin-low mammary tumors eventually emerged from this p53-deficient luminal premalignant field with 100% penetrance, apparently due to acquisition of spontaneous, recurrent mutations in p53-deficient MECs. These data support that p53-deficiency alone does not affect the fate of luminal MECs directly, but it facilitates development of mammary tumors with loss of the luminal identity after a long latency. As deficiencies of both p53 and BRCA1 in luminal MECs predispose them to development of basal-like breast cancer (rather than claudin-low cancer), we studied whether induced loss of BRCA1 in p53-deficient luminal MECs would lead to their cell fate alteration. In fact, when we induced loss of both p53 and BRCA1 in luminal MECs, we observed luminal-to-basal cell fate alteration only after a short latency. Together, our data suggest that loss of p53 in single luminal MECs leads to their clonal dominance over wild-type neighbors without directly impairing their luminal fate; it is the cooperating oncogenic events (e.g., loss of BRCA1, or acquisition of recurrent secondary mutations) that drive development of breast cancer from p53-deficient luminal cells toward different subtypes. Our results also predict that loss of p53 in luminal MECs of BRCA1 mutation carriers would not only lead to their clonal dominance, but also cause luminal-to-basal change within the mutant clones (as an early event), and ultimately development of basal-like breast cancer from these aberrant clones. This abstract is also being presented as Poster A35. Citation Format: Dongxi Xiang, Luwei Tao, Zhe Li. Elucidating mechanisms of p53-deficient breast cancer development via lineage tracing and clonal analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR07.

Experimental settings have indicated that Neurotensin regulates both satiety and breast cancer growth. Proneurotensin 1-117 (pro-NT), which stems from the same precursor as Neurotensin, has been developed as a reliable plasma surrogate biomarker for the unstable Neurotensin and has been shown to be associated with the development of incident breast cancer. Enkephalins and related opioid peptides may negatively regulate carcinogenesis and the growth of breast tumors through stimulation of the immune tumor defense system as well as direct inhibitory effects on breast cancer cells. However, little is known about their role in the development of breast cancer in humans. Enkephalin can be assessed in plasma by measuring a stable surrogate marker, Pro-Enkephalin A 119-159 (pro-ENK). OBJECTIVE: To test if plasma pro-ENK in healthy women is associated with the development of incident breast cancer and if it adds information to pro-NT for the risk prediction. DESIGN, SETTING, AND PARTICIPANTS: We measured pro-ENK and pro-NT in fasting plasma from 1929 women (mean age 58 +/- 5.9 years) of the population based Malmo Diet and Cancer Study (MDCS), who were free from breast cancer prior to the baseline exam. We used Cox proportional hazards models to relate pro-ENK and pro-NT to first breast cancer events (n = 123) within 15 years of follow-up. RESULTS: Decreasing concentrations of pro-ENK were significantly associated with the risk of women to develop breast cancer: Women belonging to quartiles 3, 2 and 1 of pro-ENK compared to those of quartile 4 had Hazard ratios (HR) for breast cancer of 1.41 (0.74-2.69), 2.3 (1.27-4.14) and 3.19 (1.82-5.62). Pro-NT: As compared to women belonging to the 1st quartile of pro-NT, women belonging to quartiles 2, 3 and 4 of pro-NT had HRs for the devlopment of breast cancer of 1.24 (0.69-2.24), 1.61 (0.92-2.82) and 2.37 (1.4-4.01). Pro-ENK significantly added prognostic value to pro-NT (p = 0.00006) and vice versa (p = 0.00002). The HR for women with pro-ENK in the 1st quartile and pro-NT in the 4th quartile (high risk group) was 4.17 (2.48-7.03) as compared to women with pro-ENK in quartiles 2-4 and pro-NT in quartiles 1-3 (low risk group). Women with one of the biomarkers in high risk still had a slightly increased risk (HR 1.71 (1.16-2.52)) as compared to the low risk group. CONCLUSION: Biomarker based risk prediction for the development of breast cancer is significantly improved, when plasma pro-ENK is added to pro-NT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-08.

Breast cancer is one of the most common malignant tumors in women, and its incidence has increased year by year, which is one of the most important causes of death among women, especially young women. Studying related cell signal transduction that affects the development and progression of breast cancer can help prevent the occurrence of breast cancer, slow down the cancer progression and improve the prognosis of patients. nitric oxide (NO) is a kind of signaling molecule. Many studies have shown that the production and expression of NO are closely related to breast cancer. NO-related cell signal transduction significantly affects the occurrence and development of breast cancer. However, the understanding of the relationship between NO and breast cancer associated cell signal transduction needs to be further improved. In this paper, the related studies on NO-related cellular signal transduction in breast cancer were reviewed with a view to improving the understanding of the development and progression of breast cancer. Key words: Nitric oxide; Breast cancer; Cell signal transduction

Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in “high-penetrance,” “moderate-penetrance,” and “low-penetrance” breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.

: Steroid hormones are involved in the development and growth of breast cancer. Drugs, which inhibit estrogen action, are commonly used to inhibit breast cancer growth. Unfortunately, most advanced breast cancer becomes resistant to estrogen treatment. Recently, many steroid receptor coactivators have been discovered and found to potentiate the transcriptional activity of steroid receptors and enhance the expression of hormone response genes. In the SRC-1 family of coactivators, AIB1 is found amplified and/or over-expressed in breast cancer specimens. To evaluate the potential roles of the SRC-1 family of coactivators in mammary tumorigenesis in vivo, we proposed to generate transgenic mice over-expression of AIB1 (SRC-3) in mammary glands. To target the expression of AIB1 in mammary gland, we placed the AIB1 transgene under the control of the MMTV-LTR promoter. Two lines of transgenic mice expressing AIB1 have been generated. Studies on these transgenic mice will help understand the development and progression of breast cancer and provide a molecular basis for designing novel strategies to curb and, ultimately, cure breast cancer.

This study aimed to identify modules associated with breast cancer (BC) development by constructing a gene co-expression network, and mining hub genes that may serve as markers of invasive breast cancer (IBC).We downloaded 2 gene expression datasets from the Gene Expression Omnibus (GEO) database, and used weighted gene co-expression network analysis (WGCNA) to dynamically study the changes of co-expression genes in normal breast tissues, ductal carcinoma in situ (DCIS) tissues, and IBC tissues. Modules that highly correlated with BC development were carried out functional enrichment analysis for annotation, visualization, and integration discovery. The hub genes detected by WGCNA were also confirmed using the Oncomine dataset.We detected 17 transcriptional modules in total and 4 — namely tan, greenyellow, turquoise, and brown — were highly correlated with BC development. The functions of these 4 modules mainly concerned cell migration (tan module, P = 3.03 × 10−4), the cell cycle (greenyellow module, P = 3.08 × 10−13), cell–cell adhesion (turquoise module, P = .002), and the extracellular exosome (brown module, P = 1.38 × 10−22). WGCNA also mined the hub genes, which were highly correlated with the genes in the same module and with BC development. The Oncomine database confirmed that the expressions levels of 6 hub genes were significantly higher in BC tissues than in normal tissues, with fold changes larger than 2 (all P < .05). Apart from the 2 well-known genes EPCAM and MELK, during the development of BC, KRT8, KRT19, KPNA2, and ECT2 also play key roles, and may be used as new targets for the detection or treatment of BC.In summary, our study demonstrated that hub genes such as EPCAM and MELK are highly correlated with breast cancer development. However, KRT8, KRT19, KPNA2, and ECT2 may also have potential as diagnostic and prognostic biomarkers of IBC.

Approximately 1.6% of adult Americans identify as transgender (TG) or nonbinary (NB) and many take gender-affirming hormone therapy (GAHT). Little data exist to inform breast and cervical cancer risks, gender-specific screening guidelines, and inclusive cancer treatment algorithms that consider GAHT. We aimed to assess TGNB persons' perceptions on breast and cervical cancer development, screening knowledge and practices, and attitude toward GAHT in the setting of a hormone receptor-positive breast cancer diagnosis. This single-institution survey study was conducted through an LGBTQ+ focused clinic from 2021 to 2022. Noncisgender patients age ≥ 18 years who were English speaking were eligible to participate. A 5-point Likert scale was used to assess concern of developing breast (all participants) and cervical cancer (those assigned female sex at birth). Demographic and quantitative variables were examined in comparison with responses via chi-squared tests. Eighty-six participants completed the survey: 43% TG men, 24% TG women, and 20% NB persons. Most (84.9%) were age < 40 years, and 86% were non-Hispanic White. The majority were unaware of breast (77%) or cervical (60%) cancer screening recommendations for their sex assigned at birth or their gender. Approximately 35% reported concern regarding breast cancer development and of those age > 40 years; only 50% had undergone screening mammography. Of those assigned female sex at birth with an intact cervix, 47% were concerned about cervical cancer development and 46.6% had a Papanicolaou smear within the past 5 years. Nearly all (87.2%) were on GAHT, and 35.1% reported they would not consider stopping GAHT if diagnosed with a hormone receptor-positive breast cancer. The findings support the need for patient and provider education on screening options and large prospective cohort data to elucidate optimal gender-specific screening guidelines and treatment algorithms.

Background:Abnormal metabolism, as measured by obesity, has been associated with an increase risk in both the development of breast cancer as well as breast cancer recurrence and death. To date, identification of a molecular link between obesity and breast cancer remains elusive. Farnesoid X receptor (FXR) is a ligand dependent transcriptional factor and plays a critical role in bile acid, cholesterol and carbohydrate metabolism. Little is known of the function of FXR in cancer although several recent studies have shown that FXR may contribute to breast, colorectal and hepatocellular cancer. Given the role of FXR in metabolism and emerging data suggesting a role for FXR in cancer, we hypothesize that expression of FXR in breast tissue may be related to metabolism. In addition, changes in FXR expression may also be associated with breast cancer development and progression.Methods:Clinical data on estrogen/progesterone receptor positive, Stage I and II breast cancer patients were extracted from an institutionally approved prospective database established in 2006. Paired formaldehyde fixed, paraffin embedded normal, in situ, and invasive tissues from these patients were identified from the COH tissue repository. Immunohistochemical staining of FXR using a validated polyclonal antibody was completed with appropriate positive and negative controls. The slides were graded independently by two investigators using an agreed upon scale to detect the percentage of positively stained cells to the nearest 10th percentile. Clinical data were correlated with expression analysis. Statistical analyses were performed with ANOVA tests followed by Fisher's t-tests for pair-wise comparisons. In determination of factors accounting for FXR expression, a multivariate analysis was completed. A p-value of 0.05 was considered significant in all analyses.Results:Paired normal tissue and invasive cancer was identified in all 43 patient specimens. In 40% (17/43) of these specimens, in situ disease was also identified. FXR expression in normal breast tissue was significantly less when compared to both invasive and noninvasive cancer (p≤ 0.001). The mean percentage of cells staining positive for FXR in normal breast tissue was 60%, non-invasive 77% and invasive 83% (p &amp;lt; 0.0001). FXR expression did not correlate with grade, histology, nodal status, Her 2 neu status, HTN, DM or hyperlipidemia in normal, in situ and invasive tissue on multivariate analysis. BMI strongly correlated with FXR expression in normal tissues (p = 0.02) and may correlate in in situ tissues (p = 0.07). However, there was no correlation of BMI with FXR expression in invasive cancer (p = 0.55).Conclusions:FXR expression is upregulated in invasive cancer and increases progressively along the continuum from normal breast tissue to malignancy. Expression of FXR correlates with BMI in normal breast tissue, suggesting that FXR may be a molecular link between obesity and the development and progression of breast cancer. Our results warrant further investigation into the relationship of FXR, obesity and breast cancer. These findings may provide support for the development of targeted FXR agents in prevention and treatment of obesity related cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5153.

Description The tumor microenvironment is an important regulator of breast cancer (BC) development. It comprises acellular and cellular factors, including immune cells like type 2 innate lymphoid cells (ILC2s). The exact molecular mechanisms of how ILC2s regulate BC immunity remain largely unknown. To analyze BC ILC2s, we used the polyoma middle T antigen transgenic mouse model, mimicking luminal BC development. Single-cell (sc)RNA sequencing and flow cytometry experiments showed that during BC development, ILC2s accumulated in the mammary fat pad (MFP) and phenotypically changed by upregulating PD-1 and Neuropilin-1 expression. To test if ILC2s directly regulate cancer cell growth, we co-cultured the BC cell line ‘VO’ with ILC2s and detected increased numbers of viable VO cells. To test the function of ILC2s in BC in vivo, we orthotopically injected the BC cell line ‘Py8119’ into the MFP of control and ILC2-deficient mice. ILC2-deficient mice developed smaller tumors, with a lower frequency of intratumoral Gr-1+CD11b+ suppressor neutrophils, compared to control mice. Co-injecting VO cells with ILC2s into the MFP of healthy mice resulted in the opposite phenotype, with bigger tumors and larger Gr-1+CD11b+ numbers in co-injected mice compared to mice injected only with VO cells. In summary, we showed that ILC2s directly and indirectly fuel BC development. Further experiments will reveal if ILC2s can be used as targets to treat BC patients. Funding Sources George E Hewitt Foundation for Medical Research Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

A number of important factors determine the risk for breast cancer, and the most important of these seem to be related to estrogen and possibly prolactin. Additional research is necessary on the role of endogenous and exogenous estrogens and the effect of diet, drugs, and other factors on the levels of estrogen and prolactin. It is unlikely that with present epidemiologic evidence, breast cancer can be prevented. We cannot alter the age of menarche, and promotion of early pregnancy to protect against breast cancer is not feasible. One risk factor that is alterable is obesity, particularly in the postmenopausal woman. The risk factors associated with exogenous estrogens following the menopause require confirmation by other studies. However, because of the strong association of these drugs with increased risk of endometrial cancer, the physician should be cautious in prescribing them.

Risk of breast cancer (BC) development reduces in regular consumption of soy protein, green tea, fruits and vegetables, dietary fibers, carotenoids, vitamin D and omega-3 fatty acids according to meta-analyses results. Objective. To describe the molecular and epigenetic mechanisms of the influence of nutritional components on breast cancer development. Materials and methods. The search was done in eLibrary, Scopus, PubMed databases for the period from 2003 to 2025 by the following keywords: «breast cancer», «food», «diet», «epigenetics», «miRNA». Results. Experimental studies indicate a variety of antitumor effects of different nutritional components on BC cells. The interaction mechanisms of resveratrol, epigallocatechin and gallic acid with mobile genetic elements that play role in pathogenesis of the disease have been identified. Nutrient materials can both stimulate and prevent the development of BC influencing the factors of apoptosis, proliferation, migration and inflammation of cells, as well as specific microRNAs expression and histone and DNA modification enzymes. Conclusion. The effect of nutrients on breast cancer development has been determined in a number of meta-analyses and confirmed in many experiments. It allows to use nutrient materials in the clinical setting in a targeted manner.

Is Dysfunction of Caveolin-1 a Link Between Systemic Sclerosis and Breast Cancer, Opening a Window on Both Etiologies?