Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The non-receptor tyrosine kinase, PTK6/BRK, is highly expressed in multiple tumor types, including prostate, ovarian, and breast cancers, and regulates oncogenic phenotypes such as proliferation, migration, and survival. PTK6 inhibition also overcomes targeted therapy resistance of HER2+ breast cancer. Although PTK6 is highly expressed in ER+ Luminal breast cancers, the role of PTK6 in this subtype has not been elucidated. In this study, we investigated the functions of PTK6 in ER+ Luminal breast cancer cells, including those that are relatively resistant to estrogen deprivation or targeted endocrine therapies used in the treatment of ER+ cancers. Enhanced expression of PTK6 in ER+ breast cancer cells enhances growth of ER+ breast cancer cells, including tamoxifen-treated cells. Downregulation of PTK6 in ER+ breast cancer cells, including those resistant to tamoxifen, fulvestrant, and estrogen deprivation, induces apoptosis, as evidenced by increased levels of cleaved PARP, and an increase in the AnnexinV+ population. PTK6 downregulation impairs growth of these cells in 3D MatrigelTM cultures, and virtually abrogates primary tumor growth of both tamoxifen-sensitive and resistant MCF-7 xenografts. Finally, we show that p38 MAPK activation is critical for PTK6 downregulation-induced apoptosis, a mechanism that we previously reported for survival of HER2+ breast cancer cells, highlighting conserved mechanisms of survival regulation by PTK6 across breast cancer subtypes. In conclusion, our studies elucidate critical functions of PTK6 in ER+ Luminal breast cancers and support PTK6 as an attractive therapeutic target for ER+ breast cancers.
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PMID:PTK6 regulates growth and survival of endocrine therapy-resistant ER+ breast cancer cells. 2916 21

Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.
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PMID:Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets. 3265 79