The impact of p53 in predicting clinical outcome of breast cancer patients with visceral metastasis

Yang, Ping; Du, Chenxing; Kwan, ML; Liang, Sixian; Zhang, G. J.

doi:10.1038/srep02246

Cited by 74 publications

(63 citation statements)

References 32 publications

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“…Previous studies have shown that in human breast cancer samples, wild-type TP53 is associated with chemotherapeutic sensitivity (18). Other studies have reported that specific TP53 mutations or variants are associated with chemotherapeutic resistance (19)(20)(21). In addition, a role for TP53 in resistance to cisplatin treatment has been identified in ovarian cancer (22).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…A higher tumour grade, negative ER and PR status, and the more aggressive basal subtype were associated with abnormal p53 immunohistochemical expression or p53-positive status [70,72,73] . With regard to early breast cancers, some scientists have reported that a p53 mutation has no influence on the outcome and therefore, the value of p53 status is too weak to be recommended as a routine marker in clinical practice [74] .…”

Section: Markers Of Apoptosis and Cell Proliferation: Ki-67 Proliferamentioning

confidence: 99%

“…In addition, sequencing of the p53 gene in all breast cancers would be expensive and time-consuming for routine practice [70,71,73] . A higher tumour grade, negative ER and PR status, and the more aggressive basal subtype were associated with abnormal p53 immunohistochemical expression or p53-positive status [70,72,73] .…”

Section: Markers Of Apoptosis and Cell Proliferation: Ki-67 Proliferamentioning

confidence: 99%

Significance of immunohistochemistry in breast cancer

Zaha

2014

WJCO

204

129

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The biological characteristics of the tumour are used to estimate prognosis and select appropriate systemic therapy for patients with (breast) cancer. The advent of molecular technology has incorporated new biomarkers along with immunohistochemical and serum biomarkers. Immunohistochemical markers are often used to guide treatment decisions, to classify breast cancer into subtypes that are biologically distinct and behave differently, and both as prognostic and predictive factors. Steroid hormone receptors, markers of tumour proliferation, and factors involved in angiogenesis and apoptosis are of scientific interest. In this review we will provide information on the immunohistochemical markers used in the management of breast cancer patients using available data from the literature. We consider the utility of established immunohistochemical markers, and discuss the challenges involved in integrating novel molecular markers into clinical practice.

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“…This eventually results in the loss of P53's transcriptional activity towards downstream effector genes involved in anticancer signaling (2,13,19). Loss of P53 activity via mutations is associated with metastasis and poor prognosis in breast cancer (20,21), pancreatic cancer (2,22), astrocytoma and oligoastrocytoma (23), and stage 1 non-small cell lung carcinoma (24). Because mutant P53 (p53 MT ) can accelerate neoplastic progression, addressing the in situ mutational status of p53 may be indispensable for successful anti-cancer therapy (2,3,25,26).…”

Section: Introductionmentioning

confidence: 99%