HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

Korkaya, Hasan; Paulson, Amanda K.; Iovino, Flora; Wicha, Max S.

doi:10.1038/onc.2008.207

Cited by 508 publications

(519 citation statements)

References 32 publications

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“…These data suggested that trastuzumab suppressed the tumorigenicity of CHGA07 primary tumor cells in vivo dramatically when administered at the same time as tumor inoculation, probably by targeting the CSC populations. Therefore, our result implied that ERBB2 signaling might contribute to the maintenance of the CSC population in gastric primary tumors, which was consistent with previous reports, in which a similar role of ERBB2 in breast cancers was reported (Korkaya et al, 2008).…”

Section: Suppression Of Tumorigenicity By Trastuzumab Prophylactic Trsupporting

confidence: 93%

“…ERBB2 overexpression could also contribute to the difference in the tumorigenicity of the CD90 þ cells isolated from different primary tumor models. Previously, it was shown that overexpression of ERBB2 not only increased the CSC population but also enhanced tumorigenicity within this population (Korkaya et al, 2008). CD90 À cells showed lower tumorigenicity than CD90 þ and unsorted tumor cells, but could still form tumors when enough CD90 À cells were implanted.…”

Section: Discussionmentioning

confidence: 94%

“…A significant correlation between ERBB2 overexpression and expression of the stem cell marker ALDH1 has been found in a series of 491 breast cancer patients (Ginestier et al, 2007). Furthermore, ERBB2 has been shown to have an important role in maintaining the CSC population in breast carcinomas (Korkaya et al, 2008;Wang et al, 2010). Interestingly, overexpression of ERBB2 could increase the proportion of stem/progenitor cells in both normal and malignant mammary epithelial cells (Korkaya et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

“…Furthermore, ERBB2 has been shown to have an important role in maintaining the CSC population in breast carcinomas (Korkaya et al, 2008;Wang et al, 2010). Interestingly, overexpression of ERBB2 could increase the proportion of stem/progenitor cells in both normal and malignant mammary epithelial cells (Korkaya et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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Section: Suppression Of Tumorigenicity By Trastuzumab Prophylactic Trsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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“…These include reduced Her2/neu autophosphorylation, binding of apigenin to Her2/neu, or interactions that block events downstream of Akt or PI3-kinase. The effect of reduced Her2/neu on tumor cell growth may relate to its potential role in maintaining human breast cancer stem cells [37]. This could be due to the robust regulation of VEGF by Her2/neu [38] which is also associated with maintaining survival of breast tumor cells [39,40].…”

Section: Discussionmentioning

confidence: 99%

Apigenin Induces Apoptosis and Blocks Growth of Medroxyprogesterone Acetate-Dependent BT-474 Xenograft Tumors

et al. 2012

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Recent clinical and epidemiological evidence shows that hormone replacement therapy (HRT) containing both estrogen and progestin increases the risk of primary and metastatic breast cancer in post-menopausal women while HRT containing only estrogen does not. We and others previously showed that progestins promote the growth of human breast cancer cells in vitro and in vivo. In this study, we sought to determine whether apigenin, a low molecular weight anticarcinogenic flavonoid, inhibits the growth of aggressive Her2/neu-positive BT-474 xenograft tumors in nude mice exposed to medroxyprogesterone acetate (MPA), the most commonly used progestin in the USA. Our data clearly show that apigenin (50 mg/kg) inhibits progression and development of these xenograft tumors by inducing apoptosis, inhibiting cell proliferation, and reducing expression of Her2/neu. Moreover, apigenin reduced levels of vascular endothelial growth factor (VEGF) without altering blood vessel density, indicating that continued expression of VEGF may be required to promote tumor cell survival and maintain blood flow. While previous studies showed that MPA induces receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rodent mammary gland, MPA reduced levels of RANKL in human tumor xenografts. RANKL levels remained suppressed in the presence of apigenin. Exposure of BT-474 cells to MPA in vitro also resulted in lower levels of RANKL; an effect that was independent of progesterone receptors since it occurred both in the presence and absence of the antiprogestin RU-486. In contrast to our in vivo observations, apigenin protected against MPA-dependent RANKL loss in vitro, suggesting that MPA and apigenin modulate RANKL levels differently in breast cancer cells in vivo and in vitro. These preclinical findings suggest that apigenin has potential as an agent for the treatment of progestin-dependent breast disease.

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A Perspective on Breast Cancer Malignant Progression

2014

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HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion

Cited by 508 publications

References 32 publications

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Apigenin Induces Apoptosis and Blocks Growth of Medroxyprogesterone Acetate-Dependent BT-474 Xenograft Tumors

A Perspective on Breast Cancer Malignant Progression

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