Breast Cancer Biology Research Articles

THU489 The Role Of Noncoding Genes With The Bidirectional Promoter In Triple-negative Breast Cancer

Abstract Disclosure: B. Yang: None. M. Sedano: None. M.V. Jimenez: None. E.I. Ramos: None. S. Gadad: None. Breast cancer is the second leading cause of cancer mortality in women after lung cancer. Breast cancer is grouped into different molecular subtypes; triple-negative breast cancer (TNBC) accounts for 20%. TNBC is a highly aggressive histologic subtype; the lack of unique therapeutic targets makes it harder to treat. Recent studies have implicated genes involved in cancers that are transcribed using a process known as divergent transcription. The expression of these genes is tightly regulated; however, many escape regulation and become aberrantly expressed in tumors. Interestingly, our genomic analysis suggests that several of these genes encode noncoding transcripts. Analysis of transcriptome from different tissue types, including cancer and normal, revealed that many are upregulated in various cancers. Selected divergent transcript, such as lncRNA67, has been completely characterized (transcription start and stop site, 5’ cap, polyA tail, and exon/intron structure) and cloned. In functional assays, overexpression of lncRNA67 regulates gene expression, cell proliferation, and tumor growth. Our molecular analyses indicate that lncRNA67 plays a vital role in triple-negative breast cancer biology. Collectively, our results suggest that divergent transcripts are an integral component of cancer biology and present a new repertoire of diagnostic and potential therapeutic targets. Presentation: Thursday, June 15, 2023

The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer.

Interleukin-33 (IL-33) has emerged as a critical cytokine in the regulation of the immune system, showing a pivotal role in the pathogenesis of various diseases including cancer. This review emphasizes the role of the IL-33/ST2 axis in breast cancer biology, its contribution to cancer progression and metastasis, its influence on the tumor microenvironment and cancer metabolism, and its potential as a therapeutic target. The IL-33/ST2 axis has been shown to have extensive pro-tumorigenic features in breast cancer, starting from tumor tissue proliferation and differentiation to modulating both cancer cells and anti-tumor immune response. It has also been linked to the resistance of cancer cells to conventional therapeutics. However, the role of IL-33 in cancer therapy remains controversial due to the conflicting effects of IL-33 in tumorigenesis and anti-tumor response. The possibility of targeting the IL-33/ST2 axis in tumor immunotherapy, or as an adjuvant in immune checkpoint blockade therapy, is discussed.

The Potentiality of Prostate-Specific Antigen as a Prognostic Biomarker in Breast Cancer.

Background Serum prostate-specific antigen (PSA) is a well-established marker that can be measured as an indicator for screening, diagnosing, and managing prostate cancer due to its advanced tissue specificity. Numerous studies have revealed that free PSA is the predominant molecular form of PSA in breast cancer cases. In contrast, total PSA is prevalent in benign breast tumor cases and healthy females. This case-control study aims to measure PSA levels among individuals with breast cancer in order to establish PSA as a prognostic biomarker. Methods The study involved 150 female subjects between the ages of 18 and 70 and was conducted between 2013 and 2014. The subjects were then categorized into three groups: those with malignant breast cancer, those with benign breast tumors, and the control group with no history of malignant or benign breast tumors. Participants were asked to complete a lifestyle questionnaire and interview using hospital medical records to establish past and pertinent patient medical history. These cases were acquired from the 7th of October Hospital's surgery department and Benghazi Central Hospital's oncology clinic in Libya. Sandwich-type ELISA's were used for PSA quantitation, while the Wilcoxon Rank-Sum test was used to identify statistically significant differences between total PSA and free PSA measurements within each patient group. Results This study did not reveal significant statistical differences in total PSA levels between breast cancer cases and control groups (p=0.200), or between breast cancer and fibroadenoma patients (p=0.472). However, there was a significant difference in F-PSA levels between breast cancer and fibroadenoma cases (p=0.0001). Neither total-PSA (p=0.200) nor F-PSA (p=0.262) levels showed significant differences between breast cancer cases and controls. This study paved the way for further investigations into PSA's role in breast cancer. Despite its limitations, it offers an opportunity to delve deeper into understanding PSA's potential role and use in breast cancer. Conclusion A comprehensive statistical analysis revealed a positive correlation between F-PSA levels and breast cancer diagnosis. The findings suggest that PSA may serve as a prognostic biomarker for breast cancer. This may contribute to improved customized treatment approaches, offering precise and accurate risk assessments, understanding breast cancer biology, and improving health outcomes for patients with breast cancer.

Single-cell RNA sequencing captures patient-level heterogeneity and associated molecular phenotypes in breast cancer pleural effusions.

Malignant pleural effusions (MPEs) are a common complication of advanced cancers, particularly those adjacent to the pleura, such as lung and breast cancer. The pathophysiology of MPE formation remains poorly understood, and although MPEs are routinely used for the diagnosis of breast cancer patients, their composition and biology are poorly understood. It is difficult to distinguish invading malignant cells from resident mesothelial cells and to identify the directionality of interactions between these populations in the pleura. There is a need to characterize the phenotypic diversity of breast cancer cell populations in the pleural microenvironment, and investigate how this varies across patients. Here, we used single-cell RNA-sequencing to study the heterogeneity of 10 MPEs from seven metastatic breast cancer patients, including three Miltenyi-enriched samples using a negative selection approach. This dataset of almost 65000 cells was analysed using integrative approaches to compare heterogeneous cell populations and phenotypes. We identified substantial inter-patient heterogeneity in the composition of cell types (including malignant, mesothelial and immune cell populations), in expression of subtype-specific gene signatures and in copy number aberration patterns, that captured variability across breast cancer cell populations. Within individual MPEs, we distinguished mesothelial cell populations from malignant cells using key markers, the presence of breast cancer subtype expression patterns and copy number aberration patterns. We also identified pleural mesothelial cells expressing a cancer-associated fibroblast-like transcriptomic program that may support cancer growth. Our dataset presents the first unbiased assessment of breast cancer-associated MPEs at a single cell resolution, providing the community with a valuable resource for the study of MPEs. Our work highlights the molecular and cellular diversity captured in MPEs and motivates the potential use of these clinically relevant biopsies in the development of targeted therapeutics for patients with advanced breast cancer.

Small-molecule inhibitors of kinases in breast cancer therapy: recent advances, opportunities, and challenges.

Breast cancer is the most common malignancy in women worldwide and despite significant advancements in detection, treatment, and management of cancer, it is still the leading cause of malignancy related deaths in women. Understanding the fundamental biology of breast cancer and creating fresh diagnostic and therapeutic strategies have gained renewed focus in recent studies. In the onset and spread of breast cancer, a group of enzymes known as kinases are extremely important. Small-molecule kinase inhibitors have become a promising class of medications for the treatment of breast cancer owing to their capacity to specifically target kinases involved in the growth and progression of cancer. The creation of targeted treatments that block these kinases and the signalling pathways that they activate has completely changed how breast cancer is treated. Many of these targeted treatments have been approved for the treatment of breast cancer as clinical trials have demonstrated their great efficacy. CDK4/6 inhibitors, like palbociclib, abemaciclib, and ribociclib, EGFR inhibitors such as gefitinib and erlotinib and HER2-targeting small-molecule kinases like neratinib and tucatinib are some examples that have shown potential in treating breast cancer. Yet, there are still difficulties in the development of targeted medicines for breast cancer, such as figuring out which patient subgroups may benefit from these therapies and dealing with drug resistance problems. Notwithstanding these difficulties, kinase-targeted treatments for breast cancer still have a lot of potential. The development of tailored medicines will continue to be fuelled by the identification of novel targets and biomarkers for breast cancer as a result of advancements in genomic and proteomic technology.

Characteristics and prognosis of adolescent and young adult breast cancer.

16 Background: Adolescent and young adult (AYA)-generation breast cancer has characteristics of high clinicopathological malignancy and poor prognosis compared to cancers of other age groups. In recent advances in cancer research, the tumor microenvironment is involved in cancer invasion. In this study, we investigated the biology of AYA-generation breast cancer and the prognostic effects of the cancer microenvironment in breast cancer patients. Methods: In the current study, we analyzed 2042 breast cancer patients with clinical and intratumoral gene expression data from the open public databases TCGA and METABRIC. Patients aged 15-39 were defined as AYA-generation breast cancer, and patients aged 40-65 as middle-aged breast cancer. Tumor biology and cancer microenvironment were assessed using gene set enrichment analysis (GSEA) and the xCell algorithm. Disease-specific survival (DSS) and disease-free survival (DFS) were used to evaluate the prognosis of AYA-generation breast cancer compared to that of middle-aged and elderly breast cancer. Results: In METABRIC, the proportion of advanced stages was higher in AYA generation breast cancer than in middle-aged and elderly breast cancer (p<0.01). However, this was not the case with TCGA cohort. In the prognostic analysis, AYA-generation breast cancer showed shortened DSS and DFS compared with middle-aged breast cancer only in METABRIC. To clarify the association between prognosis and cancer biology, we performed GSEA. AYA-generation breast cancer enriched cell proliferation-related gene sets such as E2F Targets, G2M Checkpoints, and MYC Targets V1 in METABRIC. The analysis of TCGA also confirmed this result. Interestingly, the infiltration of macrophage M1 (p<0.001) and helper T cell Th1 (p=0.007), which act as tumor suppressors, was significantly higher in AYA generation breast cancer in METABRIC cohort. In TCGA, there was only a tendency for Th1 infiltration to be high in AYA generation breast cancer. Conclusions: AYA-generation breast cancer enriched gene sets associated with cell proliferation which might explain the worse prognosis of AYA-generation breast cancer.

Effects of Hyaluronan on Breast Cancer Aggressiveness.

The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes.

Molecular mechanisms of multi-omic regulation in breast cancer.

Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease.

Obesity-associated changes in molecular biology of primary breast cancer

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients’ body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

Integrating somatic CNV and gene expression in breast cancers from women with PTEN hamartoma tumor syndrome

Women with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS) have up to 85% lifetime risk of female breast cancer (BC). We previously showed that PHTS-derived BCs are distinct from sporadic BCs both at the clinical and genomic levels. In this study, we examined somatic copy number variations (CNV) and transcriptome data to further characterize the somatic landscape of PHTS-derived BCs. We analyzed exome sequencing data from 44 BCs from women with PHTS for CNV. The control group comprised of 558 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. Here, we found that PHTS-derived BCs have several distinct CNV peaks compared to TCGA. Furthermore, RNA sequencing data revealed that PHTS-derived BCs have a distinct immunologic cell type signature, which points toward cancer immune evasion. Transcriptomic data also revealed PHTS-derived BCs with pathogenic germline PTEN variants appear to have vitamin E degradation as a key pathway associated with tumorigenesis. In conclusion, our study revealed distinct CNV x transcript features in PHTS-derived BCs, which further facilitate understanding of BC biology arising in the setting of germline PTEN mutations.

EZH2 Expression and Survival for ER+/tamoxifen Treated Breast Cancer Patients with rs2302427 C>G: A Novel Prognostic and Risk Predictive Biomarker

Overexpression of the EZH2 gene silences several genes involved in DNA repair, cell-cell adhesion, and tumor suppressor genes, resulting in the development of several types of cancers. In the present study, a genetic polymorphism analysis was performed by selecting three SNPs (rs.2302427C>G, rs.3757441C>T, and rs.6950683T>C) of the EZH2 gene based on our previous in silico studies. A total of 250 breast cancer patients and 250 healthy individuals were recruited for the study. Patients with pre-operative breast cancer with different clinical-pathological variables and age-matched healthy women were recruited for the EZH2 gene expression analysis. The genetic polymorphism analysis revealed two SNPs (rs.2302427C>G and rs.6950683T>C) of the three studied SNPs of the EZH2 gene have a protective role in all three genetic models. The haplotype analysis predicted that two haplotypes ACGT and ACGC were significantly associated with a lower risk of breast cancer. Three significant findings of the SNP rs.2302427C>G (Asp193His) i.e., protective role against breast cancer, survival advantage in ER+/tamoxifen treated breast cancer patients, and decreased expression due to the presence of mutant GG genotype, suggests considering it as an important prognostic biomarker for a good survival outcome of breast cancer patients treated with ER+/tamoxifen. Compared with other studies, the other SNP rs.3757441T>C was observed to have a protective effect in breast cancer biology but plays an antagonistic role in colorectal cancer (CRC) biology. To our knowledge, this is the first detailed study on computationally validated EZH2 SNPs in breast cancer.

Sociodemographic and clinicopathologic factors of triple negative breast cancer at an academic urban safety-net hospital.

1090 Background: Racial disparities in breast cancer in the United States is a persistent and ongoing problem. Decades of research is derived from large population based data sets and little is published with granular detail of specific, actionable factors to target for interventions. From a large urban safety-net hospital, we evaluate sociodemographic and clinicopathologic factors on survival outcomes of triple negative breast cancer. Methods: We conducted a single-institution retrospective study of patients with invasive breast cancer, diagnosed and treated between January 2010 and December 2021 at an academic safety-net hospital where insurance systems allow for access and treatment for all patients. Demographic, tumor and treatment characteristics were obtained. Chi-square and ANOVA were used to examine associated factors among White, Black, and other races. Survival was analyzed using the Kaplan-Meier estimator and log-rank test. Significant risk factors were identified with Cox regression analysis. Results: 251 women with invasive triple negative breast cancer were diagnosed and treated during the study period. Median age was 58 years, 68.9% were non-white, and 64.9% were publicly insured or uninsured patients. Median time from diagnosis to treatment initiation was 29 days and follow up period was 1392 days. Having a non-English primary language and living in areas with lower socioeconomic indices are observed in non-White patients (P=0.003, 0.033) and predictive of a higher clinical stage at presentation (P=0.011, 0.021). Black patients were diagnosed at higher histologic grade (Black: 82.4%, White: 79.7%; P=0.003) and White patients were more likely to change facility during the treatment course (White: 32.4%, Black: 16.03%; P=0.005). No significant racial disparities were observed in time to treatment, recurrence rate, and overall survival. Among patients indicated for adjuvant therapies, including chemotherapy, immunotherapy, and radiation, rates of recommendation and completion of therapy did not vary by race. Five year survival did not significantly vary by race when adjusted for demographic and clinicopathologic factors. Conclusions: At an academic urban safety-net hospital where access to diagnostic and treatment resources are comparable across patient populations, no racial disparities were seen in treatment, recurrence, and survival outcomes. Further research on racial differences in breast cancer biology and health behaviors may improve understanding of triple negative disease or mitigate later stage diagnosis.

Distribution and outcomes of HER2-low and HER2-zero metastatic breast cancer in Black and younger women.

1109 Background: Black and younger patients with breast cancer (BC) have higher mortality. This racial disparity has been attributed to different BC biology, access to care, and treatment. With the advent of new antibody-drug conjugates (ADC) for metastatic BC (MBC), “HER2-negative” has been subdivided into HER2-low (IHC 1+ or 2+/ISH-negative) and HER2-0 (IHC 0). Little is known about these subcategories among Black and younger women with MBC. Methods: Clinical characteristics, treatment, and outcomes of patients diagnosed with HER2-negative MBC between 2011-2022 and with follow-up through a progression-free survival event on first-line therapy (PFS1) were retrieved from the UNC Metastatic Breast Cancer Database; hormone receptor (HR) and HER2 categories were by clinical criteria from the pathology report. Analyses were limited to HER2-negative BC and stratified/controlled by HR status. Fisher’s exact tests were used to compare HER2 status across race and age. The Kaplan Meier method and log-rank tests, as well as Cox proportional hazards models estimated PFS1. Results: The cohort included 772 MBC patients (56% HER2-low and 44% HER2-0), 22% Black women and 30% < 50 years old at MBC diagnosis. There were no differences in proportion with HER2-low by race or age (p>0.5). Patients with HER2-low had better observed median PFS1 compared to HER2-0, however, most of these differences were non-significant: overall (HR+ 12.2 vs 9.8m, p=0.11, HR- 4.3 v 3.3m, p=0.29) and within race and age categories (see table). In Cox modeling, Black women had worse PFS1 (p=0.03), that was no longer apparent after adjusting for HR status (p=0.1), there was no difference by age. Patients with HER2-0 had worse PFS1 (p=0.0005), which remained after adjusting for HR status (p=0.05). In a multivariable model comparing HER2-0 to HER2-low, adjusting for race and HR status, PFS1 remained shorter in the HER2-0 group (hazard ratio: 0.84, CI 0.692 – 1.015, p=0.07). Among those treated with uniform first-line therapy, better PFS1 was observed in HER2-low disease. This included 137 HR+ MBC treated with ET + CDK4/6i (mPFS1 14.3 v 10.3m, p=0.33) and 170 HR- MBC treated with chemotherapy (mPFS1 4.0 v 3.1m, p=0.22) with no variation by race or age. Conclusions: Within HER2-negative MBC, distribution of HER2-low and HER2-0 cancers does not differ by race and age. The clinical benefit of first-line therapy is strongly driven by HR status regardless of race and age, and is greater in HER2-low cancers although this cohort did not include HER2-directed ADCs. [Table: see text]

Special issue. De-escalation of loco-regional treatment in breast cancer: Time to find the balance? Partial breast irradiation.

Breast cancer is the most common cancer in women worldwide. Over the past few decades, remarkable progress has been made in understanding the biology and pathology of breast cancer. A personalized conservative approach has been currently adopted addressing the patient's individual risk of relapse. After postoperative whole breast irradiation for early-stage breast cancer, a rate of recurrences outside the initial tumour bed lower than 4% was observed. Thus, the highest benefits of breast irradiation seem to result from the dose delivered to the tissue neighbouring the tumour bed. Nonetheless, reducing treatment morbidity while maintaining radiation therapy's ability to decrease local recurrences is an important challenge in treating patients with radiation therapy. In this regard, strategies such as partial-breast irradiation have been developed to reduce toxicity without compromising oncologic outcomes. According to the national and international published guidelines, clinical oncologists can refer to specific dose/fractionation schedules and eligible criteria. However, there are still some areas of open questions. Breast cancer represents a multidisciplinary paradigm; it should be considered a heterogeneous disease where a "one-treatment-fits-all" approach cannot be considered an appropriate option. This is a wide overview on the main partial breast irradiation advantages, risks, timings, techniques, and available recommendations. We aim to provide practical findings to support clinical decision-making, exploring future perspectives, towards a balance for optimisation of breast cancer.

Selection biases in the systematic collection of breast biobank specimens.

6533 Background: A breast biopsy tissue biobank is a valuable resource for studying breast cancer biology and treatment response. However, underrepresentation of patient populations in biobanks limits the generalizability of findings. The aim of this study was to assess potential age and racial/ethnic disparities in the recruitment process for an institutional breast biopsy tissue bank. Methods: Ultrasound-guided (USG) research biopsy cores were collected immediately after routine clinical biopsy from January 2019 to October 2022 at a large academic center. Study eligibility included patients (pts) aged > 18 years undergoing USG clinical breast biopsy with a radiographically evident mass ≥ 0.6 cm in the longest dimension. Eligible pts, identified by a research associate on the day of the biopsy, were invited to participate at the discretion of the radiologist performing the biopsy. Those approached either consented or declined a research biopsy. Demographic and clinical data of eligible pts were extracted from the EMR. Results: 2449 pts underwent USG breast biopsy and 1309 were deemed eligible for a research biopsy. Of the eligible population, 564 (43%) consented to the study, 322 (25%) declined, and 423 (32%) were not approached. Consented pts were younger compared to those who declined or to those not approached (median age 49, 51, and 51 years, respectively; p = .01). Comparison of study groups by age and race categories are shown in the table. Pts > 70 were less likely to be approached compared to pts < 70 (p = .01). However, The likelihood of pts being approached to consent did not differ significantly with age (p=.09 ). Of the eligible pts, 951 (73%) were White, 327 (25%) were non-White (10% Asian, 8% Black, 1% Hispanic, and 7% other race), and race was unknown for 31 (2%) pts. White and non-White pts were equally likely to be approached (p = .3). However, approached non-White pts were significantly less likely to consent compared to White pts (p =.01). Within the non-White population, Black pts were more likely to decline a research biopsy, with only 50% of approached Black pts consenting compared to 66% of White pts, 61% of Asian pts and 55% of pts of other race. Conclusions: We found disparities based on age and race/ethnicity in participation in a breast biopsy tissue biobank. Older pts were less likely to be offered participation but equally likely to consent when invited, while Black pts were equally likely to be offered participation, but less likely to consent when invited, compared to other racial subgroups. Our findings support targeted interventions to increase participation across diverse subgroups of pts. [Table: see text]

Prognostic Significance of P21 Protein in Breast Cancer

Abstract Breast cancer is the most common malignancy in women. Bearing in mind these circumstances, a review of new molecular mechanisms underlying breast cancer progression, resistance and various aspects of existing therapeutic methods would lead to new insights for biologists and clinicians. In this regard, we conducted a study covering recent advances in breast cancer biology with a focus on the p21 protein. The study included 147 patients diagnosed with invasive breast cancer. The presence of non-invasive lesions was noted in each invasive breast cancer and surrounding tissue. p21 expression was determined by reading the percentage of nuclear expression in epithelial cells of invasive breast cancer and non-invasive lesions. Results showed that expression of p21 increases with the progression of cytological changes in the epithelium; it is significantly higher in invasive breast cancer compared to non-invasive lesions (p<0.001). There is a difference in p21 expression between different molecular subtypes of breast cancer (p=0.004). Statistically significantly higher values of p21 expression were observed in those breast cancers that showed overexpression of HER2 compared to HER2-negative tumors (p=0.001). Depending on Ki67 expression, the highest p21 expression is in the group with high Ki67 expression values (p=0.019). The increase in p21 expression in tumor cells was accompanied by a statistically significantly reduced expression of ER (p=0.015, ρ=-0.225) and PR (p=0.027, ρ−0.205). p21 protein plays an important role in proliferation, malignant transformation, as well as in progression from non-invasive lesions to invasive breast cancer.

Calcium Homeostasis in the Development of Resistant Breast Tumors.

Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.

Molecular characteristics and prognosis of breast cancer patients with different level of HER2 positivity after adjuvant and neoadjuvant chemotherapy.

HER2-low breast cancer (BC) has renewed interests of researchers worldwide. Here, we aimed to investigate the clinicopathological characteristics of patients with HER2-low, HER2-0 and HER2 ultra-low BC and make conclusion. We collected cases of patients who were diagnosed as BC at Jingling General hospital. Immunohistochemistry was used to redefine HER2 scores. Kaplan-Meier methods and Cox proportional hazards regression analysis were used to compare survival. We found that HER2-low BC was more frequent in hormone receptor (HR)-positive BC patients and was associated with fewer T3-T4, lower breast conserving surgery rate and higher adjuvant chemotherapy rate. HER2-low BC patients had better overall survival (OS) compared to HER2-0 BC in premenopausal and stage II BC. Furthermore, HER2-0 BC patients had lower Ki-67 expression levels compared to HER2-ultra low and HER2-low BC in HR-negative BC. HER2-0 BC patients also had worse OS rate compared to those with HER2-ultra low BC in HR-positive BC. Finally, HER2-0 BC patients showed a higher pathological response rate compared to those with HER2-low BC after neoadjuvant chemotherapy. These findings suggest that HER2-low BC has distinct biology and clinical features compared to HER2-0 BC, and more investigation is needed to understand the biology of HER2-ultra low BC.

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity.

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms. Therefore, deciphering the interactions between the distinct cell types, their spatial organization and their specific contribution to tumor growth and drug sensitivity is still a major challenge. Dissecting intra-tumor heterogeneity is currently an urgent need to better define breast cancer biology and to develop therapeutic strategies targeting the microenvironment as helpful tools for combined and personalized treatment. In this review, we analyze the mechanisms by which the tumor microenvironment affects the characteristics of tumor heterogeneity that ultimately result in drug resistance, and we outline state of the art preclinical models and emerging technologies that will be instrumental in unraveling the impact of the tumor microenvironment on resistance to therapies.