TGF-  Biology in Mammary Development and Breast Cancer

Moses, Harold L.; Barcellos‐Hoff, Mary Helen

doi:10.1101/cshperspect.a003277

Cited by 198 publications

(187 citation statements)

References 100 publications

Supporting

Mentioning

183

Contrasting

Order By: Relevance

Section: Ink4amentioning

confidence: 99%

“…39 However, epithelial cancer cells progressively acquire resistance to the cytostatic effects driven by TGFβ, and the tumor progresses towards advanced stages. 39 Loss of REST protein, or the expression of aberrant REST transcript variants encoding truncated REST proteins, has been reported in several types of human malignancies of epithelial origin, including breast, lung, and colon cancers. [6][7][8] In breast cancer, the loss of FL REST protein, in favor of a shorter carboxyterminal truncated form has been described in a small fraction of cases and is associated with disease recurrence and poor prognosis.…”

Section: Ink4amentioning

confidence: 99%

See 1 more Smart Citation

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

View full text Add to dashboard Cite

REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway. Cell Death and Differentiation (2015) 22, 1353-1362 doi:10.1038/cdd.2014; published online 23 January 2015The transcription factor REST was originally discovered as a repressor of neuronal differentiation genes in non-neuronal lineages. Therefore, REST is considered as a master regulator of neurogenesis in development and maintenance of gene silencing. [1][2][3][4] Recently, it has been recognized that aberrant REST function also has a role in human malignancies, largely depending on the cellular context. 5 Focal genomic deletions targeting the REST locus have been found in colon adenocarcinoma and REST protein expression is often lost in small cell lung carcinoma cells. 6,7 In breast cancer, the loss of full-length (FL) REST protein is associated with disease recurrence and poor prognosis.8 However, the underlying mechanism of how REST protects against transformation in epithelial tissues has remained largely elusive.We have previously implicated the testis-specific protein, Y-encoded-like (TSPY-L) family of genes in cancer by identifying TSPYL5 expression as a prognostic marker of poor clinical outcome in breast cancer.9 TSPYL5 can interfere with p53-dependent cell-cycle arrest and oncogene-induced senescence triggering p53 ubiquitination and protein degradation.9 Besides TSPYL5, the TSPYL family of genes includes several other members (four coding genes and one pseudogene) whose functions are still unknown. All five proteins (TSPYL1, TSPYL2, TSPYL4, TSPYL5, and TSPYL6) are characterized by a predicted nucleosome assembly protein (NAP) domain, although functional evidence of NAP activity has not been reported of any of the TSPYL family members. TSPYL2, which shares only partial homology with TSPYL5, has been proposed as a candidate tumor suppressor in carcinoma cells.10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor comple...

show abstract

Section: Ink4amentioning

confidence: 99%

Section: Ink4amentioning

confidence: 99%

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, a number of patients exhibited poor survival due to chemoresistance and metastasis (3). Transforming growth factor β1 (TGF-β1) is a well-known factor in regulating breast epithelial cell development, differentiation and carcinogenesis, and tumor progression (4). TGF-β1 was initially identified as a regulator of breast cancer over two decades ago (5).…”

Section: Introductionmentioning

confidence: 99%

miR‑21 is involved in transforming growth factor β1‑induced chemoresistance and invasion by targeting PTEN in breast cancer

Dai

Mao

et al. 2017

Oncol Lett

View full text Add to dashboard Cite

Abstract. Transforming growth factor β1 (TGF-β1) has been associated with poor outcomes in patients with breast cancer. However, the functions and underlying molecular mechanisms of TGF-β1 in breast cancer remain unknown. Therefore, the present study aimed to identify the effects of components of the TGF-β/microRNA (miR-)21/phosphatase and tensin homolog (PTEN) signaling axis in breast cancer. TGF-β1 was identified to upregulate the expression of miR-21, and miR-21 was demonstrated to be significantly upregulated in breast cancer tissues compared with benign proliferative breast disease. In addition, the expression of miR-21 was significantly associated with increased TGF-β1 and clinical characteristics in patients, including tumor grade and lymph node metastasis (all P<0.05). Furthermore, in the breast cancer MCF-7 cell line, TGF-β1 was revealed to induce the expression of miR-21 in a doseand time-dependent manner. The results of the present study additionally demonstrated that increased miR-21, in response to TGF-β1 signaling, was associated with tumor invasion and chemoresistance in vitro. In addition, suppression of PTEN was mediated by TGF-β1-induced expression of miR-21 in breast cancer cells and using a miR-21 inhibitor revitalized the expression of PTEN. The results of the present study explored the functions of TGF-β1-stimulated expression of miR-21 to suppress the PTEN axis, which promotes breast cancer progression

show abstract

“…), impaired intratumoral drug delivery is an important physiological factor contributing toward chemoresistance (1,2). TGF-β is an important regulator of normal mammary gland development and function, as well as of the progression of mammary carcinomas (3)(4)(5)(6)(7)(8). Although the role of TGF-β in tumor progression and metastasis has been studied extensively, little is known about its impact on drug delivery.…”

mentioning

confidence: 99%

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Liu

Liao

Diop-Frimpong

et al. 2012

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

288

234

View full text Add to dashboard Cite

Although the role of TGF-β in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.breast cancer | vessel normalization | drug delivery B reast cancer is the second leading cause of cancer death in women, with most fatalities resulting from a failure to control metastatic disease with systemically administered therapies. In addition to the induction of cellular resistance mechanisms (decreased apoptosis, increased drug efflux, etc.), impaired intratumoral drug delivery is an important physiological factor contributing toward chemoresistance (1, 2). TGF-β is an important regulator of normal mammary gland development and function, as well as of the progression of mammary carcinomas (3-8). Although the role of TGF-β in tumor progression and metastasis has been studied extensively, little is known about its impact on drug delivery.Transport of a therapeutic agent from the circulation to cancer cells is a three-step process. Systemically administered drugs must (i) travel to different regions within a tumor via the vascular network; (ii) cross the vessel wall; and finally (iii) diffuse through the interstitial space to reach the tumor cells, with each step being hindered by the presence of an abnormal vasculature and/or matrix (1, 2, 9, 10). Tumor blood vessels are structurally and functionally abnormal, characterized by increased permeability and heterogeneous perfusion. Poor vascular perfusion decreases drug delivery and, as a result, impairs the efficacy of blood-borne antitumor agents (1, 11). In addition, the dense collagen-rich interstitial matrix further hinders drug transport to tumor cells-a feature especially relevant to larger therapeutics, such as nanoparticles (1-100 nm) (1, 10, 12, 13). The dense collagen matrix also contributes to solid stress, which compresses tumor vessels (14). Hence, depleting collagen will reduce stress and open up compressed vessels. TGF-β is a negative regulator of pericyte recruitment during blood vessel stab...

show abstract

TGF- Biology in Mammary Development and Breast Cancer

Cited by 198 publications

References 100 publications

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

miR‑21 is involved in transforming growth factor β1‑induced chemoresistance and invasion by targeting PTEN in breast cancer

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Contact Info

Product

Resources

About