Stacey DaCosta Byfield

Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β

We used 2D-cocultures employing fibroblasts of different genetic backgrounds and MCF10A-derived human breast epithelial cells of increasingly malignant potential to investigate tumor-stroma interactions in breast cancer and to identify possible signaling pathways involved. Tumor cells induced expression of matrix-metalloproteinase 9 (MMP-9) in fibroblasts in a pattern dependent on the degree of their malignancy. In-situ zymography localized the main gelatinolytic activity around stromal cells in cocultures and xenografted tumors. Use of Smad3 knockout fibroblasts, small molecule inhibitors, and neutralizing antibodies showed that MMP-9 expression was induced by tumor cell-derived TNF-α and TGF-β, dependent on Smad-, Ras-, and PI3-kinase-signaling, and likewise modulated by subsequent HGF- and EGF-signaling. Together, our results indicate that MMP-9 levels in tumor fibroblasts are regulated by a complex tumor-stroma cross-talk, involving multiple ligands and cellular signaling pathways.

Smad-Binding Defective Mutant of Transforming Growth Factor β Type I Receptor Enhances Tumorigenesis but Suppresses Metastasis of Breast Cancer Cell Lines

The role of transforming growth factor β (TGF-β) in carcinogenesis is complex, with tumor suppressor and pro-oncogenic activities depending on the particular tumor cell and its stage in malignant progression. We previously have demonstrated in breast cancer cell lines that Smad2/3 signaling played a dominant role in mediating tumor suppressor effects on well-differentiated breast cancer cell lines grown as xenografts and prometastatic effects on a more invasive, metastatic cell line. Our present data based on selective interference with activation of endogenous Smad2 and Smad3 by stable expression of a mutant form of the TGF-β type I receptor (RImL45) unable to bind Smad2/3 but with a functional kinase again show that reduction in Smad2/3 signaling by expression of RImL45 enhanced the malignancy of xenografted tumors of the well-differentiated MCF10A-derived tumor cell line MCF10CA1h, resulting in formation of larger tumors with a higher proliferative index and more malignant histologic features. In contrast, expression of RImL45 in the more aggressive MCF10CA1a cell line strongly suppressed formation of lung metastases following tail vein injection. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-β in these cells. Using an in vitro assay, we further show that non-Smad signaling pathways, including p38 and c-Jun NH2-terminal kinase, cooperate with TGF-β/Smads in enhancing migration of metastatic MCF10CA1a cells, but that, although necessary for migration, these other pathways are not sufficient for metastasis.

ReCAP: Treatment Patterns and Cost of Care Associated With Initial Therapy Among Patients Diagnosed With Operable Early-Stage Human Epidermal Growth Factor Receptor 2-Overexpressed Breast Cancer in the United States: A Real-World Retrospective Study.

PURPOSE Overexpression of the human epidermal growth factor receptor 2 (HER2) protein negatively affects survival in breast cancer. This study aimed to assess real-world treatment patterns and costs associated with resected nonmetastatic HER2-positive breast cancer in the United States. PATIENTS AND METHODS Commercially insured patients with HER2-positive breast cancer were identified from oncology registry data linked to a large US commercial administrative claims database. Treatment patterns and health care use and costs in the initial phase of care were examined. RESULTS Among the 915 patients who met the study criteria, 662 (72%) were hormone receptor (HR) positive, and 253 (28%) were HR negative. Overall, 72% (n = 662) of patients received HER2-targeted therapy (HR positive, 69% v HR negative, 80%; P < .01), specifically trastuzumab. The most common treatment regimens, regardless of HR status, were carboplatin, docetaxel, and trastuzumab (47% of patients) during neoadjuvant therapy and carboplatin, docetaxel, and trastuzumab ± hormone therapy (30% of patients) during adjuvant therapy. Overall unadjusted cost of treatment per patient per month (HR positive,

Clinical and economic outcomes by first-line treatment among women with HR+/HER2– metastatic breast cancer in a large US health plan database

11,906 v HR negative,

Abstract P4-15-10: Initial therapy among patients newly diagnosed with operable early stage human epidermal growth factor receptor 2-overexpressed (HER2+) breast cancer in the US: A real-world retrospective study

14,367; P < .001) was mainly cancer related (HR positive,

Abstract P3-07-23: Patient characteristics, clinical and economic outcomes of women with first-line therapy for HR+/HER2- metastatic breast cancer in a large US managed care health plan: Chemotherapy first vs. no chemotherapy first

10,513 v HR negative,

Abstract P3-07-24: Clinical characteristics and treatment utilization by tumor subtype among metastatic breast cancer patients in a large US managed care health plan

13,073; P < .001). Adjusted 12-month cost was

SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7

176,779 (HR positive,

Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis

167,088 v HR negative,

Reduction in Smad2/3 Signaling Enhances Tumorigenesis but Suppresses Metastasis of Breast Cancer Cell Lines

180,226; P > .05). CONCLUSION Although trastuzumab-based therapy is considered standard of care among patients with HER2-positive early-stage breast cancer, approximately 28% of these patients did not receive HER2-targeted therapy. Additional studies are warranted to examine whether patients who have not received targeted therapy are eligible for and would benefit from an HER2-targeted approach.