Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges.

Changes in Breast Cancer Risk Associated with Benign Breast Disease from 1967 to 2013.

Background: Benign breast disease (BBD) increases breast cancer (BC) risk progressively for women diagnosed with non-proliferative (NP) change, proliferative disease without atypia (PDWA), and atypical hyperplasia (AH). Leveraging data from 18,704 women in the Mayo BBD Cohort (1967-2013), we evaluated temporal trends in BBD diagnoses and how they have influenced associated BC risk over four decades.

Methods: BC risk trends associated with BBD were evaluated using standardized incidence ratios (SIRs) and age-period-cohort modeling across four eras-pre-mammogram (1967-1981), pre-core needle biopsy (CNB) (1982-1992), transition to CNB (1993-2001), and CNB era (2002-2013).

Polygenic risk scores stratify breast cancer risk among women with benign breast disease.

Purpose: Most breast biopsies are diagnosed as benign breast disease (BBD), with 1.5- to fourfold increased breast cancer (BC) risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in BC risk assessment of these patients.

Microcalcifications in benign breast biopsies: association with lesion type and risk.

Purpose: To characterize associations of microcalcifications (calcs) with benign breast disease lesion subtypes and assess whether tissue calcs affect risks of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC).

Methods: We analyzed detailed histopathologic data for 4,819 BBD biopsies from a single institution cohort (2002-2013) followed for DCIS or IBC for a median of 7.4 years for cases (N = 338) and 11.

Multiplex Digital Spatial Profiling in Breast Cancer Research: State-of-the-Art Technologies and Applications across the Translational Science Spectrum.

While RNA sequencing and multi-omic approaches have significantly advanced cancer diagnosis and treatment, their limitation in preserving critical spatial information has been a notable drawback. This spatial context is essential for understanding cellular interactions and tissue dynamics. Multiplex digital spatial profiling (MDSP) technologies overcome this limitation by enabling the simultaneous analysis of transcriptome and proteome data within the intact spatial architecture of tissues.

Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma.

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era.

Importance: Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD.

Objectives: To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy.

Inflammation, Infiltration, and Evasion-Tumor Promotion in the Aging Breast.

Breast cancer is a significant cause of morbidity and mortality in women, with over two million new cases reported worldwide each year, the majority of which occur in post-menopausal women. Despite advances in early detection and treatment, approximately one-third of patients diagnosed with breast cancer will develop metastatic disease. The pathogenesis and progression of breast cancer are influenced by a variety of biological and social risk factors, including age, ethnicity, pregnancy status, diet, and genomic alterations.

Benign Breast Disease, NSAIDs, and Postmenopausal Breast Cancer Risk in the CPS-II Cohort.

Abstract: Nonsteroidal anti-inflammatory agents (NSAID) are associated with modest inconsistent reductions in breast cancer risk in population-based cohorts, whereas two focused studies of patients with benign breast disease (BBD) have found lower risk with NSAID use. Given that BBD includes fibroinflammatory lesions linked to elevated breast cancer risk, we assessed whether NSAID use was associated with lower breast cancer risk among patients with BBD.Participants were postmenopausal women in the Cancer Prevention Study-II (CPS-II), a prospective study of cancer incidence and mortality, who completed follow-up surveys in 1997 with follow-up through June 30, 2015.

Immune cells are increased in normal breast tissues of BRCA1/2 mutation carriers.

Purpose: Breast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control. We hypothesized that if immunosurveillance promotes tumor suppression, then normal/benign breast lobules from BRCA carriers may demonstrate higher immune cell densities.

Methods: We assessed immune cell composition in normal/benign breast lobules from age-matched women with progressively increased breast cancer risk, including (1) low risk: 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, (2) intermediate risk: 15 women with biopsy-identified benign breast disease (BBD), and (3) high risk: 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes.

Reproductive risk factors associated with breast cancer in young women by molecular subtype.

Background: Few studies have examined detailed features of pregnancy and the postpartum period as potential risk factors for early onset breast cancer (BC) by molecular subtype. These data may have value for improving risk assessment and prevention.

Methods: We surveyed parous enrollees in the prospective Mayo Clinic Breast Disease Registry (MCBDR) who had been diagnosed with BC at age <55 years between 2015 and 2020.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence.

Background: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described.

Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood.

Activity-based protein profiling reveals active serine proteases that drive malignancy of human ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is an understudied poor prognosis subtype of ovarian cancer lacking in effective targeted therapies. Efforts to define molecular drivers of OCCC malignancy may lead to new therapeutic targets and approaches. Among potential targets are secreted proteases, enzymes which in many cancers serve as key drivers of malignant progression.

Serum hormone levels and normal breast histology among premenopausal women.

Purpose: Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations.

Lower Exome Sequencing Coverage of Ancestrally African Patients in The Cancer Genome Atlas.

Background: In the United States, cancer disproportionately impacts Black and African American individuals. Identifying genetic factors underlying cancer disparities has been an important research focus and requires data that are equitable in both quantity and quality across racial groups. It is widely recognized that DNA databases quantitatively underrepresent minorities.

Engineering of tissue inhibitor of metalloproteinases TIMP-1 for fine discrimination between closely related stromelysins MMP-3 and MMP-10.

Matrix metalloproteinases (MMPs) have long been known as key drivers in the development and progression of diseases, including cancer and neurodegenerative, cardiovascular, and many other inflammatory and degenerative diseases, making them attractive potential drug targets. Engineering selective inhibitors based upon tissue inhibitors of metalloproteinases (TIMPs), endogenous human proteins that tightly yet nonspecifically bind to the family of MMPs, represents a promising new avenue for therapeutic development. Here, we used a counter-selective screening strategy for directed evolution of yeast-displayed human TIMP-1 to obtain TIMP-1 variants highly selective for the inhibition of MMP-3 in preference over MMP-10.

Automated quantification of levels of breast terminal duct lobular (TDLU) involution using deep learning.

Convolutional neural networks (CNNs) offer the potential to generate comprehensive quantitative analysis of histologic features. Diagnostic reporting of benign breast disease (BBD) biopsies is usually limited to subjective assessment of the most severe lesion in a sample, while ignoring the vast majority of tissue features, including involution of background terminal duct lobular units (TDLUs), the structures from which breast cancers arise. Studies indicate that increased levels of age-related TDLU involution in BBD biopsies predict lower breast cancer risk, and therefore its assessment may have potential value in risk assessment and management.

Somatic mutations in benign breast disease tissues and association with breast cancer risk.

Background: Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC.

Methods: A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC, and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes.

MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence.

Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models.

Aurora-A kinase oncogenic signaling mediates TGF-β-induced triple-negative breast cancer plasticity and chemoresistance.

Triple-negative breast cancer (TNBCs) account for 15-20% of all breast cancers and represent the most aggressive subtype of this malignancy. Early tumor relapse and progression are linked to the enrichment of a sub-fraction of cancer cells, termed breast tumor-initiating cells (BTICs), that undergo epithelial to mesenchymal transition (EMT) and typically exhibit a basal-like CD44/CD24 and/or ALDH1 phenotype with critical cancer stem-like features such as high self-renewal capacity and intrinsic (de novo) resistance to standard of care chemotherapy. One of the major mechanisms responsible for the intrinsic drug resistance of BTICs is their high ALDH1 activity leading to inhibition of chemotherapy-induced apoptosis.