In breast cancer (BrCa), overexpression of the nuclear co-activator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating BrCa cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating CSF1 expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and BrCa cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes BrCa metastasis, offering a novel therapeutic target for impeding this process.
Aromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor-positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor-responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer. Cancer Res; 72(2); 548-59. Ó2011 AACR.
Twist1 promotes epithelial-mesenchymal transition, invasion, metastasis, stemness, and chemotherapy resistance in cancer cells and thus is a potential target for cancer therapy. However, Twist1-null mice are embryonic lethal, and people with one Twist1 germline mutant allele develop Saethre-Chotzen syndrome; it is questionable whether Twist1 can be targeted in patients without severe adverse effects. We found that Twist1 is expressed in several tissues, including fibroblasts of the mammary glands and dermal papilla cells of the hair follicles. We developed a tamoxifen-inducible Twist1 knockout mouse model; Twist1 knockout in 6-week-old female mice did not affect mammary gland morphogenesis and function during pregnancy and lactation. In both males and females, the knockout did not influence body weight gain, heart rate, or total lean and fat components. The knockout also did not alter blood pressure in males, although it slightly reduced blood pressure in females. Although Twist1 is not cyclically expressed in dermal papilla cells, knockout of Twist1 at postnatal day 13 (when hair follicles have developed) drastically extended the anagen phase and accelerated hair growth. These results indicate that Twist1 is not essential for maintaining an overall healthy condition in young and adult mice and that loss of function facilitates hair growth in adulthood, supporting Twist1 as a preferential target for cancer therapy.
Membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP-14) drives fundamental physiological and pathological processes, due to its ability to process a broad spectrum of substrates. Because subtle changes in its activity can produce profound physiological effects, MT1-MMP is tightly regulated. Currently, many aspects of this regulation remain to be elucidated. It has recently been discovered that O-linked glycosylation defines the substrate spectrum of MT1-MMP. We hypothesized that a mutual interdependency exists between MT1-MMP trafficking and glycosylation. Lectin precipitation, metabolic labeling, enzymatic deglycosylation, and sitedirected mutagenesis studies demonstrate that the LL Proteases regulate processes as diverse as apoptosis, blood clotting, angiogenesis, embryogenesis, and inflammation. Furthermore, proteolytic activity shapes the most distinctive and devastating feature of invasive cancers: their ability to break the boundaries of intact tissue structures and form colonies at a distance from their origin (1, 2). Proteolytic activity constitutes a final common pathway in the development of all invasive neoplasms (2-5). Other characteristics of cancers, their limitless replicative potential, sustained angiogenesis, self sufficiency in growth signals, and the ability to evade apoptosis, are also affected by proteolytic activity, if not entirely dependent upon it (2, 5-7). Matrix metalloproteinases (MMPs), 2 a family of zincbinding proteases, have long been associated with metastasis and tumor cell invasion. Elevated levels of MMPs have been verified in almost all human cancers (7,8).Mechanisms that confine proteolytic activity in the pericellular microenvironment have been found to be essential regulators of tumor microecology and are prerequisites for tumor cell invasion (9). The most obvious mediators of such localized proteolytic activity are the transmembrane-and glycosylphosphatidylinositol-anchored membrane type (MT) MMPs (10, 11). MT1-MMP (MMP-14) is considered the prototype of these membrane-tethered proteases due to its broad spectrum proteolytic capabilities and prominent involvement in cancer spreading (12)(13)(14).Because MMPs have broadly overlapping substrate targets, most MMP knockout mice display no dramatic phenotypes (4, 15). So far, only the loss of MT1-MMP has been demonstrated to be incompatible with normal postnatal development. MT1-MMP-deficient mice display a variety of bone and joint disorders, including dwarfism, osteopenia, and arthritis (15).The majority of MMPs and most other proteases are secreted as inactive pro-enzymes that undergo limited proteolysis for their activation. MT1-MMP is activated intracellularly and has the potential to activate other proteases such as MMP-2 on the cell surface. This makes it an important trigger of proteolytic cascades. In general, the activity of MT1-MMP is closely controlled post-translationally by its activation, inactivation, various endogenous inhibitors, oligomerization, protein trafficking, and glycosylation (4). It is this last ...
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