Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

González-Reyes, Salomé; Marín, Laura; González, Lucía; González, Luis O.; Casar, José M. del; Lamelas, Marı́a L.; González-Quintana, José Manuel

doi:10.1186/1471-2407-10-665

Cited by 198 publications

(190 citation statements)

References 48 publications

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“…TLR4 also has been identified at the protein level in breast epithelial tumor cells (5). In contrast to its role in tumor-associated immune cells, TLR4 promotes growth (6) and chemotherapeutic resistance (7,8) in ER-negative breast cancer cell lines, in accordance with studies of ovarian cancer (9,10).…”

mentioning

confidence: 59%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

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

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Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.reast cancer has one of the highest incidence rates of cancer in women worldwide, with more than 1.5 million women diagnosed with the disease in 2012. Owing to its high incidence, breast cancer is also one of the leading causes of cancer-related deaths, with 40,000 women predicted to die of the disease in 2014 in the US alone. The diagnosis and treatment of breast cancer has been significantly improved by the identification of three major subtypes of the disease based on receptor expression: estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [tumors lacking ER, progesterone receptor (PR), and HER2]. Of these subtypes, ER-positive breast cancer accounts for 70-80% of all diagnosed breast tumors.ER-positive breast cancer is largely responsive to endocrine therapy; however, intrinsic or acquired resistance occurs in onethird of cases and contributes significantly to breast cancerassociated mortality. Therefore, identifying therapeutic targets to prevent ER-positive breast cancer mortality is a major focus of scientific investigation. ER-positive breast tumors with a high mutation load are associated with poor patient survival, and a high mutation load likely affects the response to endocrine therapy (1). Because known drivers of endocrine resistance (e.g., PR negativity and HER2 amplification) are not enriched in this subset, the identification of no...

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confidence: 59%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

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

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“…This process results in a cytokine profile that is associated with immune tolerance, cancer progression and propagation of the tumor microenvironment [22] . In fact, recent studies by our group revealed that breast carcinomas with high TLR3 expression by tumor cell or with high TLR4 expression by MICs were significantly associated with higher probability of metastasis [65] . Likewise, we found that samples of prostate carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9.…”

Section: Clinical Relevance Of Inflammatory Components In Tumor Progrmentioning

confidence: 99%

Inflammation and cancer

Eiró

Vizoso²

2012

WJGS

132

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“…Though TLRs are expressed in macrophage, dendridic cell, and other innate immune cell, it was also found the high expression of TLRs in breast cancer cell [15]. Knockdown of TLR4 impairs the proliferation and survival of breast cancer cells.…”

Section: Figure 1 Tlrs Familymentioning

confidence: 99%

Toll-like Receptor: Breast Cancer Development and Immunotherapy

Manna¹

2016

Arch Can Res

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Breast cancer is well known leading causes of mortality in the females. Current studies have suggested that the imbalances in inflammatory and immune-associated proteins may also give rise to breast cancer and disease progression. Toll like receptors (TLRs) are essential components of innate immune system that protect the host against bacterial and viral infection. It not only express in innate immune cell, its expression also found in breast cancer cells. Activation of TLRs leads to the activation of inflammatory pathways. Recent reports provide such evidences, which suggest the important role of TLRs in breast cancer pathogenesis and recurrence. TLRs are not only involved in cancer development, but also involve in anticancer immunotherapy. There are some agonists and antagonist of TLRs, used in anticancer immunotherapy, is targeted in clinic successfully.

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Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis

Cited by 198 publications

References 48 publications

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Inflammation and cancer

Toll-like Receptor: Breast Cancer Development and Immunotherapy

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