Clinical and pathological features of breast disease in Cowden's syndrome: An underrecognized syndrome with an increased risk of breast cancer

Schrager, Carolina A.; Schneider, Douglas; Gruener, Alexandra C.; Tsou, Hui C.; Peacocke, Monica

doi:10.1016/s0046-8177(98)90389-6

Cited by 168 publications

(101 citation statements)

References 24 publications

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“…Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K͞PKB pathway, has been increasingly implicated in breast carcinogenesis. Cowden's syndrome, which, in affected family members, is associated with an increased risk of breast cancer, is due to germ-line mutations in PTEN (39). Although PTEN mutations are rare in spontaneous breast cancers (40), a significant number of breast tumors have low PTEN levels (41).…”

Section: Discussionmentioning

confidence: 99%

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation

Holbro

Beerli²,

Maurer³

et al. 2003

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

848

720

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ErbB2 is a receptor tyrosine kinase whose activity in normal cells depends on dimerization with another ligand-binding ErbB receptor. In contrast, amplification of c-erbB2 in tumors results in dramatic overexpression and constitutive activation of the receptor. Breast cancer cells overexpressing ErbB2 depend on its activity for proliferation, because treatment of these cells with ErbB2-specific antagonistic antibodies or kinase inhibitors blocks tumor cells in the G 1 phase of the cell cycle. Intriguingly, loss of ErbB2 signaling is accompanied by a decrease in the phosphotyrosine content of ErbB3. On the basis of these results, it has been proposed that ErbB3 might be a partner for ErbB2 in promoting cellular transformation. To test this hypothesis and directly examine the role of the ''kinase dead'' ErbB3, we specifically ablated its expression with a designer transcription factor (E3). By infection of ErbB2-overexpressing breast cancer cells with a retrovirus expressing E3, we show that ErbB3 is an essential partner in the transformation process. Loss of functional ErbB2 or ErbB3 has similar effects on cell proliferation and cell cycle regulators. Furthermore, expression of constitutively active protein kinase B rescues the proliferative block induced as a consequence of loss of ErbB2 or ErbB3 signaling. These results demonstrate that ErbB2 overexpression and activity alone are insufficient to promote breast tumor cell division. Furthermore, we identify ErbB3's role, which is to couple active ErbB2 to the phosphatidylinositol 3-kinase͞protein kinase B pathway. Thus, the ErbB2͞ErbB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation.T he family of ErbB receptor tyrosine kinases includes four members: epidermal growth factor (EGF) receptor͞ErbB1, ErbB2, ErbB3, and ErbB4. Binding of peptides of the EGFrelated growth factor family to the extracellular domain of ErbB receptors results in the formation of homo-and heterodimers. Ligand binding induces the intrinsic receptor kinase activity, ultimately leading to stimulation of intracellular signaling cascades (1, 2). The physiological role of ErbB2, in the context of ErbB ligand signaling, is to serve as a coreceptor (3, 4). In fact, ErbB2 appears to be the preferred partner of the other ligandbound ErbBs (5, 6). The importance of heterodimer-mediated signaling in normal development is obvious from studies in genetically modified mice. This is particularly true for ErbB2͞ ErbB3 and ErbB2͞ErbB4 heterodimers. Loss of ErbB2 or ErbB3 has a similar impact on neuronal development (7), whereas loss of ErbB2 or ErbB4 has major effects on heart development (8, 9).A wealth of clinical data has demonstrated that ErbB receptor tyrosine kinases, in particular ErbB1 and ErbB2, have roles in human cancer development, thus making them attractive targets for cancer therapies (10-13). ErbB2 overexpression, generally attributable to gene amplification, occurs in 25-30% of breast cancer and correlates with shorter time to relapse and lower overall survival (1...

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Section: Discussionmentioning

confidence: 99%

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation

Holbro

Beerli²,

Maurer³

et al. 2003

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

848

720

View full text Add to dashboard Cite

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“…The highest risk is of breast cancer in females, approximately 70%. 11 We assigned the gene responsible for CD to chromosome 10q23 by an extensive linkage study in 12 families. 12 The gene encoding PTEN (alternatively named MMAC1 or TEP1), a dual specificity phosphatase identified within the critical region, [13][14][15] was shown to be involved by the identification of germline mutations present in a number of CD patients.…”

Section: Introductionmentioning

confidence: 99%

Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations

Nelen¹,

et al. 1999

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Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichilemmomas. Several neurological symptoms are also part of CD with megalencephaly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of developing malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found with higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were identified in both familial and sporadic CD patients. We identified eight PTEN mutations, of which seven were novel, in 13 CD patients. Combined with previous data we have identified 17 independent CD mutations. Gross DNA alterations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutations are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical features of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, it is likely that we have identified the majority of CD patients in the Netherlands. From this we estimate that CD has a prevalence of about 1 in 250 000 in the Dutch population with a low mutation frequency.

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“…Among these patients, evidence of breast hamartoma was found in 17 and of malignancy, mainly ductal carcinoma, in 14 out of 19 women (Schrager et al 1998). Male breast cancer has also been reported (Fackenthal et al 2001).…”

Section: Cowden Diseasementioning

confidence: 92%

Reproductive disturbances in multiple neuroendocrine tumor syndromes

Lytras

Tolis²

2009

Endocrine-Related Cancer

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Clinical and pathological features of breast disease in Cowden's syndrome: An underrecognized syndrome with an increased risk of breast cancer

Cited by 168 publications

References 24 publications

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation

The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation

Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations

Reproductive disturbances in multiple neuroendocrine tumor syndromes

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