Invasive Ductal Carcinoma Metastasis Research Articles

Abstract 3645: OSM-induced LOXL2 expression hinges on upregulation of c-Myc and promotes tumor growth and metastasis, IL-1beta plays synergistic role in LOXL2 expression

Abstract Ductal carcinoma is the most commonly diagnosed breast cancer in women, the presence of metastases drops patient five-year survival from 95% to an abysmal 27%. This makes studying the mechanisms that promote metastasis of critical importance. Research shows that the extracellular matrix (ECM) of the tumor microenvironment (TME) plays an important role in invasive ductal carcinoma (IDC) progression and metastasis. Specifically; the density, stiffness, and orientation of collagen I fibers in the stroma all impact IDC motility, invasion, and metastasis. Lysyl oxidase-like 2 (LOXL2) is a secreted enzymatic protein that is implicit in ECM remodeling. By catalyzing an oxidative reaction in peptidyl lysine/hydroxylysine present on collagen I fibers, LOXL2 initiates crosslinking of the fibers. Our previous publication demonstrates that interleukin-6-related pro-inflammatory cytokine signaling, specifically oncostatin M (OSM), led to the overexpression and secretion of the LOXL2 enzyme. This increased the metastatic potential of IDC cells by promoting the crosslinking and alignment of collagen I fibers, which in turn led to increased invasion in 3D collagen I matrices. Thus, we hypothesize that OSM-induced LOXL2 expression, secretion, and subsequent collagen I fiber crosslinking and alignment, leads to an increase in IDC metastasis. In vivo studies utilizing nude athymic mice injected with either MCF7-Luc-EV control or MCF7-Luc-OSM overexpressing cells were performed in conjunction with LOXL2 inhibition using specially designed chow containing either LOXL2 SMI or control. Further analysis of OSM signaling pathways was performed in MCF7 and MDA-MB-468 IDC cells to determine mechanism for OSM induction of LOXL2. Our studies demonstrate that canonical OSM signaling pathways (pERK, pSTAT3, and pAKT) all contribute to LOXL2 expression in MCF7 cells suggesting a possible mediator protein we identified as c-Myc. Furthermore, OSM-induced LOXL2 played a significant role in OSM promoted tumor growth and metastasis as LOXL2 inhibition led to decreased tumor size and far less metastatic lesions. We also analyzed and confirmed a synergistic interaction between OSM and interleukin-1beta (IL-1β) in LOXL2 expression. These results confirm the significance of LOXL2 expression in OSM promoted metastasis and suggests LOXL2 would be an important target for future breast cancer therapies, specifically in patients with elevated levels of OSM. Furthermore, the synergistic interaction between OSM and IL-1β in LOXL2 expression suggests that patients with high levels of both cytokines are at even greater risk of metastasis, making these great markers for determining at risk IDC patients. Citation Format: Simion Dinca, Cody Wolf, Laura Bond, Cheryl Jorcyk. OSM-induced LOXL2 expression hinges on upregulation of c-Myc and promotes tumor growth and metastasis, IL-1beta plays synergistic role in LOXL2 expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3645.

Breast Cancer to Meningioma: A Rare Case of Tumor-to-Tumor Metastasis

Tumor-to-tumor metastasis (TTM) is defined as the hematogenous metastasis within a primary host tumor from a donor neoplasm. Since there is insufficient evidence regarding the pathophysiology, clinical course, and management of TTM, there are no precise guidelines for its management. A 73-year-old female patient diagnosed with breast cancer was found to have convexity meningioma. Since the size of tumor and peritumoral brain edema increased during follow-up period, the meningioma was treated with surgical resection. Postoperatively, histopathologic examination confirmed metastasis of invasive ductal carcinoma within a secretory meningioma. The final diagnosis was TTM of breast cancer in meningioma. Here, we report a rare case of intra-meningioma metastasis and a review of literature to provide a better understanding of this rare phenomenon.

Cutaneous metastasis of invasive ductal carcinoma on FNAC: A case report

The cutaneous metastasis is a late uncommon manifestation of cancer and indicates poor prognosis. The cutaneous metastasis can be a first presentation of underlying malignancy. The FNAC is an easy tool for rapid diagnosis of cutaneous metastasis. A 47-year-old female, known case of invasive ductal carcinoma presented to hospital with history of multiple nodular skin lesions over the body varying in size from 0.5-1.5 cm from past 2 months. The smears were cellular and comprises of loose clusters and singly scattered atypical epithelial cells, displaying moderate degree of pleomorphism with mild amount of cytoplasm, large irregular nucleus with fine to coarse chromatin, inconspicuous to conspicuous nucleoli and occasional atypical mitosis against a lipohemorrhagic background. The diagnosis of metastatic deposits of invasive ductal carcinoma was rendered. The clinical diagnosis of metastatic deposits can be challenges, especially in case of distant metastasis or when the cutaneous metastasis is the first presentation. The cutaneous metastasis can be confused clinically as adnexal lesion. The use of special stains and immunohistochemical markers can aid in diagnosis.

Keep scalpel sheathed: A metastatic invasive ductal carcinoma mimics primary linitis plastica

Though differentiating gastric metastasis of breast cancer from primary gastric cancer is challenging, it is of paramount importance because the treatments to these two diseases are completely different. A wrong diagnosis could lead the patient to unnecessary gastrectomy. It is more challenging for gastric metastasis of invasive ductal carcinoma given its rarity. Here we reported a case whose diagnosis was made correctly with complementary lab studies, clinically well‐informed Pathologist and special immunohistochemical staining. Correct diagnosis and following treatment saved the patient from gastrectomy and prolonged her survival.

Gallbladder Metastases of Invasive Ductal Carcinoma of the Breast Resected 9 Years after Initial Mastectomy

Gallbladder Metastases of Invasive Ductal Carcinoma of the Breast Resected 9 Years after Initial Mastectomy

Neck metastasis of invasive ductal carcinoma of breast causing voice change: a case report

We present a metastatic carcinoma from the breast to the neck soft tissue around common carotid artery, with a rare finding of voice change. A 60 year-old female patient presented with voice change for 7 months. Neck ultrasound revealed a soft tissue mass between internal jugular vein and common carotid artery. Result of fine needle aspiration biopsy was a metastatic carcinoma. Computed tomography and magnetic resonance image revealed 2.5 x 3.0 cm sized irregular marginated soft tissue mass in right lower neck encasing common carotid artery and internal jugular vein. Surgical resection was performed and pathologic result with immunohistochemical analysis confirmed the diagnosis of a metastatic invasive ductal carcinoma originated from breast.

Downregulation of klotho β is associated with invasive ductal carcinoma progression.

Klotho β (KLB) is a single-pass transmembrane protein measuring 1,043 amino acids in length that shares 41.2% homology with klotho α (KLA). KLB is a co-receptor and key regulator of the fibroblast growth factor receptor 4 (FGFR4) pathway. KLB interacts with FGFR4 to induce apoptosis and inhibit the proliferation of hepatoma cells, and KLA has been demonstrated to be a tumor suppressor in human breast cancer; however, little is known regarding the role of KLB in breast cancer. In the present study, through an immunohistochemical analysis of invasive ductal carcinoma tissue arrays, low KLB expression was identified in invasive ductal carcinoma samples compared with paired adjacent non-tumorous breast tissues (82 cases). In invasive ductal carcinoma tissues, KLB expression was negatively associated with pathological grade and lymph node metastasis. In 42 cases of paired microdissected breast specimens, the condition of the KLB gene allele was examined to determine the loss of heterozygosity (LOH), and selective LOH was identified at the KLB locus in 57.1% of primary tumors. These data suggest that KLB may be associated with the progression and metastasis of invasive ductal carcinoma, and therefore have clinical and therapeutic importance.

High Expression of Urokinase-Type Plasminogen Activator Is Associated with Lymph Node Metastasis of Invasive Ductal Carcinoma of the Breast.

PurposeIn the present study, we evaluated the levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) by performing immunohistochemical staining to determine whether they were reliable prognostic markers in patients with breast cancer.MethodsDemographic and clinicopathological parameters of 214 patients with invasive ductal carcinoma (IDC) and 80 patients with ductal carcinoma in situ (DCIS) who were diagnosed and treated from 2006 to 2010 were analyzed. Tissue microarray was constructed and immunohistochemical staining was performed for each specimen.ResultsUnivariate analyses showed that age at diagnosis, history of hormone replacement therapy, radiation therapy, skin and chest wall invasion, Paget disease, lymphovascular invasion, estrogen receptor positivity, and triple-negative subtype were significantly associated with patient prognosis (p<0.005). Patients with DCIS showed higher PAI-1 expression than patients with IDC (82.5% and 36.2%, respectively; p=0.012). Lymph node metastasis was more frequent in patients with high uPA levels than in patients with low uPA levels (p=0.001).ConclusionOur results suggested that PAI-1 was involved in tumor progression in the early stages of breast cancer, such as DCIS. In addition, our results suggested that high uPA levels were associated with the lymph node metastasis of IDC.

Isolated Uterine Metastasis of Invasive Ductal Carcinoma

Introduction. Most common metastasis sites of breast cancer are the lungs, bones, liver, and brain, whereas uterine involvement by metastatic breast disease is rare. Metastatic carcinoma of the uterus usually originates from other genital sites, most commonly being from the ovaries. Invasive lobular carcinoma spreads to gynecologic organs more frequently than invasive ductal carcinoma. Case Report. A 57-year-old postmenopausal woman was diagnosed with breast carcinoma 2 years ago and modified radical mastectomy was performed. Pathological examination of tumor revealed invasive ductal carcinoma, stage IIIc. She presented with abdominal pain and distension. Diagnostic workup and gynecologic examination revealed lesions that caused diffuse thickening of the uterus wall. Endometrial sampling was performed for confirmation of the diagnosis. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Breast carcinoma metastases in endometrium and myometrium were confirmed histopathologically and immunohistochemically. Conclusion. We herein report the first case of isolated uterine patient who had invasive ductal carcinoma of breast.

Significance of Loss of Heterozygosity in Predicting Axillary Lymph Node Metastasis of Invasive Ductal Carcinoma of the Breast

Invasive ductal carcinoma (IDC) of breast metastatic to axillary lymph node (ALN) is a critical factor in determining stage and is a strong predictor of disease prognosis and survival. We studied ALN metastasis using a combined histopathologic/molecular approach to gain insights into the pathobiology implications. Fourteen patients with IDC with positive ALN and 19 with negative ALN were retrieved. Analysis of 17 polymorphic microsatellite repeat markers targeting 1p34-36, 3p24-26, 5q23, 9p21, 10q23, 17p13, 17q12, 17q21, 21q22, and 22q13 was carried out in DNA isolated from primary tumors and metastatic tumors. ALN metastasis correlated with fractional mutation rate of primary and ALN metastatic tumors, primary tumor size, and nuclear grade, and did not correlate with expression of estrogen receptor, progesterone receptor, and Her2/neu. Loss of heterozygosity (LOH) detected at 1p34-36, 3p24-26, 9p21, 10q23, 17p13, 17q12, 21q22, and 22q13 may play an important role in the development and aggressiveness of IDC, and LOHs at 1p34-36, 17p13, and 22q13 may play an important role in metastasis. None of the LOHs were shared by all the tumors, suggesting that IDC develops through various pathways that have unique and personalized patterns of mutational changes, although they share similar morphology. Detection of LOH in IDC is not only useful in studying oncogenesis, but also predicting aggressiveness and ALN metastasis.

Highly Proliferative Fibroblasts Forming Fibrotic Focus Govern Metastasis of Invasive Ductal Carcinoma of the Breast

We have already reported that invasive ductal carcinomas (IDCs) with fibrotic focus (FF) have more aggressive characteristics than those without FF. FF is composed of a mixture of fibroblasts and various amounts of collagen fibers, suggesting that highly proliferative fibroblasts forming FF increase the malignant potential of IDCs with FF. The purpose of this study was to examine whether there is a difference of proliferative activity of fibroblasts forming and not forming FF, which plays an important role in the tumor progression of IDCs. Two hundred three consecutive cases of IDC of the breast surgically treated at the National Cancer Center Hospital East formed the basis for this study. The proliferative activity of the fibroblasts forming the FF was immunohistochemically evaluated by using mouse MIB-1 monoclonal antibody against Ki-67 antigen. The MIB-1 labeling index (LI) is the percentage of fibroblasts forming FF that have positively stained nuclei, and 300 fibroblasts were counted in each FF. The significance of the proliferative activity of fibroblasts forming FF with regard to lymph node metastasis (LNM) or distant-organ metastasis (DOM) was compared with well-known prognostic parameters. Multivariate analysis demonstrated that high MIB-1 LI of fibroblasts forming FF significantly increased the relative risk of LNM and the hazard rate of DOM (P < .001 and P = .009). The present study indicated that the metastatic ability of IDCs with FF is highly dependent on the proliferative activity of the fibroblasts forming FF.

Proliferative Activity of Intratumoral Fibroblasts Is Closely Correlated with Lymph Node and Distant Organ Metastases of Invasive Ductal Carcinoma of the Breast

Mitotic figures of fibroblasts are seen within invasive ductal carcinoma (IDC) of the breast. This suggests that the proliferative activity of fibroblasts may play an important role in IDC tumor progression. The purpose of this study was to examine whether the proliferative activity of fibroblasts can predict lymph node metastasis (LNM) or distant-organ metastasis (DOM) of IDCs. Two hundred four consecutive patients with IDC of the breast surgically treated at the National Cancer Center Hospital East constituted the basis of this study. Proliferative activity of fibroblasts was immunohistochemically evaluated by the mouse MIB-1 monoclonal antibody against Ki-67 antigen. The MIB-1 labeling index was the percentage of fibroblasts with positively stained nuclei, and fields for cell counting were selected in inner and outer areas within IDCs. In both areas, 300 fibroblasts were counted in each high-power field. The significance of proliferative activity of fibroblasts on LNM or DOM was compared with well-known prognostic parameters. Multivariate analyses demonstrated that a MIB-1 labeling index of more than 10% of fibroblasts in the inner area of IDCs significantly increased the relative risk of LNM and hazard rate of DOM (P < 0.001 and P = 0.007, respectively). The present study indicated that the metastatic ability of IDCs is closely dependent on proliferative activity of fibroblasts in the inner area.

Histological factors associated with initial bone metastasis of invasive ductal carcinoma of the breast.

Bone is one of the most common sites of recurrence of breast cancer. Therefore, it would be clinically very useful if breast cancers with a high probability of bone metastasis (BM) could be identified by histopathological examination of the primary lesions. To elucidate histological characteristics associated with predisposition to initial BM, we examined nine histopathological parameters in the primary lesions of 110 invasive ductal carcinomas (IDCs) of the breast with 0 to 3 regional node metastases. These cases had recurrence between 4 months and 10.1 years after the initial radical surgery. The first metastatic site was bone in 24 cases, whereas other sites were involved in 86 cases. IDCs growing in a strand growth pattern or with fibrotic focus (FF) had a significantly higher frequency of initial BM than those growing in a non‐strand growth pattern or without FF, respectively. Strand growth pattern was a significant predictor of the initial BM in multivariate analysis. In all 54 IDCs that developed BM during the follow‐up period, osteolytic metastasis was significantly more frequent in the group with FF than in that without FF. This study demonstrated that strand growth pattern and the presence of FF are significant histopathological factors associated with initial BM. The combination of those predictive factors along with prognostic factors may provide a useful approach to identify patients at high risk for initial BM, enabling early treatment for the recurrent cancer.

Characterization and frequency distribution of lymphoreticular infiltrates in axillary lymph node metastases of invasive ductal carcinoma of the breast

Characterization and frequency distribution of lymphoreticular infiltrates in axillary lymph node metastases of invasive ductal carcinoma of the breast

Characterization and frequency distribution of lymphoreticular infiltrates in axillary lymph node metastases of invasive ductal carcinoma of the breast.

One hundred and seventy-five axillary lymph nodes containing metastatic deposits from 46 invasive ductal carcinomas of the breast were evaluated histologically and immunohistologically. The study yielded the following results: (1) tumor-infiltrating lymphoreticular cells preferentially accumulated in the stromal bands; the tumor foci generally showed a considerably lower degree of infiltration; (2) in most cases, monocytes/macrophages (Mono 1+) represented the overwhelming majority of tumor-infiltrating cells; (3) next in frequency were T-lymphocytes (Leu-1+), especially CD4+ lymphocytes (Leu-3a+), while CD8+ lymphocytes (Leu-2a+) mostly occurred only in moderate numbers; (4) B-lymphocytes (To15+), plasma cells, natural killer cells (Leu-7+), tissue mast cells, and T-accessory reticulum cells (OKT 6+) were observed mostly in low or very low numbers, while eosinophils were nearly absent and B-accessory reticulum cells (Ki-M4+) were totally absent from the lymphoreticular infiltrates. Definite conclusions regarding the functional properties of the tumor-infiltrating cells cannot be drawn from an immunohistologic analysis in situ alone, but the preferred localization of most tumor-infiltrating cells in the stroma does not support an intensive interaction between the host defenses and the metastatic tumor.