High-resolution mapping of molecular events associated with immortalization, transformation, and progression to breast cancer in the MCF10 model

Worsham, Maria J.; Pals, Gerard; Schouten, Jan P.; Miller, Fred R.; Tiwari, Nivedita; Spaendonk, Rosalina van; Wolman, Sandra R.

doi:10.1007/s10549-005-9077-8

Cited by 78 publications

(82 citation statements)

References 48 publications

(56 reference statements)

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“…However, activation of TGF-β signaling in MCF10A breast epithelial cells after RAS-G12V expression promotes increased invasion rather than senescence. Two independent reports have uncovered MYC amplification in MCF10A cells, a genetic alteration that we demonstrate can prevent OIS in response to RAS-G12V (32,33). TGF-β signaling has been shown to suppress transcription of the MYC gene, and defective repression of MYC is frequently observed in breast cancer cells that are insensitive to TGF-β (34,35).…”

Section: Discussionmentioning

confidence: 54%

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Cipriano¹,

Kan²,

Graham³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/ RB-and p53-independent OIS in response to oncogenic RAS that requires TGF-β signaling. Suppression of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor, use of a TGF-β type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-β signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-β receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. (ii) constitutive growth signaling, (iii) unlimited replication potential, and (iv) invasive potential (1). Early studies using normal mouse cells indicated that a limited set of genetic manipulations could confer neoplastic potential (2). However, normal human cells have been more difficult to transform to malignancy, indicative of their more stringent tumor-suppressive pathways. Extensive study of cultured human mammary epithelial cells (HMEC) has identified two senescence barriers. One involves the stress-associated induction of the cyclin-dependent kinase inhibitor p16 before attaining critically short telomeres. This stasis barrier can be overcome by inhibiting p16, allowing continued proliferation, which results in agonescence, a proliferative barrier mediated by telomere depletion (3). Additionally, the ability of dysregulated oncogenic signaling to induce senescence in human cells has implicated oncogene-induced senescence (OIS) as an important tumor-suppressive barrier. A number of recent studies have demonstrated the physiological relevance of OIS in human tumorigenesis and in vivo tumor mouse models (4). Additionally, the presence of senescent cells in benign but not advanced tumors argues that OIS serves as an early tumorsuppressive barrier that needs to be dismantled for full oncogenic progression (4). In human fibroblasts, OIS could be bypassed by disabling p16 or molecular components of the DNA damage response (DDR), including ATM, CHK2, or p53, before RAS, MOS, or STAT5 overexpression (5-9). However, OIS in HMEC has been shown to be independent of p53 and the p16-RB pathway after oncogenic RAF-1 expression (10). The contrasting responses between epithelial and fibroblast cells argue that the signaling networks responsible for OIS have tissue specificity. Indeed, fibrob...

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Section: Discussionmentioning

confidence: 54%

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Cipriano¹,

Kan²,

Graham³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast to PDGFRA mRNA levels, we did not observe any relationship between breast cancer progression and tamoxifen resistance for PDGFRB. HRAS is rarely mutated in breast cancer (Hollestelle et al 2007), but high mRNA levels were found to be associated with increased metastatic potential in untreated patients in line with its reported role in progression and invasion (Watson et al 1991, Gelmann et al 1992, Moon et al 2000, Worsham et al 2006). No associations of RAF1 or NRG1 mRNA levels with tamoxifen resistance were observed in our study.…”

Section: Discussionmentioning

confidence: 79%

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Agthoven¹,

Sieuwerts²,

Meijer³

et al. 2010

Endocrine-Related Cancer

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Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct antiestrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

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“…As suggested by Heng, 19 it may be that tumors are so genetically unstable that they may regain their lost genes as they progress. In a breast cancer cell line, Worsham et al 20 found that several homozygous losses in key genes during the early stages were restored to their diploid status when the cell line became more virulent. Although the morphologic instability of these tumors is most likely paralleled by genetic heterogeneity between the primary tumor and metastases, the presence of mutations and genetic aberrations that are conserved along the thyroid carcinoma progression spectrum offers hope that these tumors may be amenable to target therapy.…”

Section: Discussionmentioning

confidence: 99%

Histopathologic characterization of radioactive iodine‐refractory fluorodeoxyglucose‐positron emission tomography‐positive thyroid carcinoma

Rivera

Ghossein

Schöder

et al. 2008

Cancer

191

130

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BACKGROUND.Radioactive iodine‐refractory (RAIR) 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) positive thyroid carcinomas represent the major cause of deaths from thyroid carcinomas (TC) and are therefore the main focus of novel target therapies. However, to the authors' knowledge, the histology of FDG‐PET‐positive RAIR metastatic thyroid carcinoma has not been described to date.METHODS.Metastatic tissue from RAIR PET‐positive patients identified between 1996 and 2003 at the study institution were selected for histologic examination. The biopsied metastatic site corresponded to a FDG‐PET positive lesion sampled within 2 years (87% of which were sampled within 1 year) of the PET scan. Detailed microscopic examination was performed on the metastatic deposit and the available primary tumors. Poorly differentiated thyroid carcinomas (PDTC) were defined on the basis of high mitotic activity (≥5 mitoses/10 high‐power fields) and/or tumor necrosis. Other types of carcinomas were defined by conventional criteria. The histology of the metastases and primary were analyzed, with disease‐specific survival (DSS) as the endpoint.RESULTS.A total of 70 patients satisfied the selection criteria, 43 of whom had primary tumors available for review. Histologic characterization of the metastasis/recurrence in 70 patients revealed that 47.1% (n = 33 patients) had PDTC, 20% (n = 14 patients) had the tall cell variant (TCV) of papillary thyroid carcinoma, 22.9% (n = 16 patients) had well‐differentiated papillary thyroid carcinoma (WDPTC), 8.6% (n = 6 patients) had Hurthle cell carcinoma (HCC), and 1.4% (n = 1 patient) had anaplastic carcinomas. The histopathologic distribution of the tumor in the primaries was: PDTC, 51%; TCV, 19%; WDPTC, 23%; and widely invasive HCC, 7%. A differing histology between the primary tumor and metastasis was observed in 37% of cases (n = 16 patients). In the majority of instances (63%; 10 of 16 patients) this was noted as transformation to a higher grade. Of the primary tumors classified as PTC, 70% progressed to more aggressive histotypes in the metastasis. Tumor necrosis and extensive extrathyroid extension in the primary tumor were found to be independent predictors of poorer DSS in this group of patients (P = .015). Approximately 68% of the PDTC primary tumors were initially classified by the primary pathologist as better‐differentiated tumors on the basis of the presence of papillary and/or follicular architecture or the presence of typical PTC nuclear features.CONCLUSIONS.Several observations can be made based on the results of the current study. The majority of metastases in patients with RAIR PET‐positive metastases are of a histologically aggressive subtype. However, well‒differentiated RAIR metastatic disease is observable. Poorly differentiated disease is underrecognized in many cases if defined by architectural and nuclear features alone. The presence of tumor necrosis was found to be a strong predictor of aggressive behavior, even within this group of clinically aggressive tumors. Finally, there is a significant amount of histologic plasticity between primary tumors and metastases that may reflect the genetic instability of these tumors. Cancer 2008. © 2008 American Cancer Society.

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High-resolution mapping of molecular events associated with immortalization, transformation, and progression to breast cancer in the MCF10 model

Cited by 78 publications

References 48 publications

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Histopathologic characterization of radioactive iodine‐refractory fluorodeoxyglucose‐positron emission tomography‐positive thyroid carcinoma

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