The estrogen receptor plays a critical role in the pathogenesis and clinical behavior of breast cancer. To better understand the molecular basis of estrogen-dependent forms of this disease we studied gene expression profiles from 53 primary breast cancer biopsies. Gene expression data for more than 7000 genes were generated from each tumor sample with oligo microarrays. A standard correlation-clustering algorithm identified 18 genes that co-clustered with estrogen receptor alpha. Eleven of these genes had previously been associated with estrogen regulation or breast tumorigenesis including trefoil factor 1 and estrogen regulated LIV-1. Additional study of these 18 genes may further delineate the role of estrogen receptor in breast cancer, generate new predictive biomarkers for response to endocrine therapies and identify novel therapeutic targets. The Pharmacogenomics Journal ( BACKGROUNDThe estrogen receptor is a ligand-activated transcription factor containing hormone binding, DNA binding and transcription activation domains. 1 It is expressed in normal breast and 50-80% of breast cancers, depending on the assay used. 2-4 Estrogen receptor (ER) is a favorable prognostic factor and ER positive malignancies have a lower risk of relapse and a better overall survival. 5 However, ESR1 analysis is most useful in predicting response to endocrine therapies, although approximately half of all ER-positive cancers do not respond to antiestrogens or estrogen deprivation therapies. 6 The molecular basis for ESR1-positive, endocrine therapy-resistant disease is not well understood. Somatic mutations in ESR1 are rare, even in breast cancers that have acquired resistances to endocrine therapies. This finding has focused attention on other mechanisms, including the overexpression of tyrosone-kinase linked growth factor receptors, transcriptional coactivators such as AIB1 (amplified in breast cancer 1) or cell cycle regulators including Cyclin D1. Additional possibilities include mutations in other genes involved in the regulation of estrogen-dependent growth.Expression of the estrogen-regulated genes, progesterone receptor (PGR) and trefoil factor 1 (TFF1 or PS2) indicate the presence of a functional and activated ER. 7 Both of these proteins are predictive biomarkers for breast cancer endocrine therapy, although less valuable than ER in distinguishing estrogen-dependent from estrogen-independent breast cancer. The use of PGR improves upon the predictive value of ER alone, yet ෂ 40% of tumors that express both ER and PGR fail to respond to endocrine treatments in the metastatic setting. 8 Similarly, TFF1 is associated with a good prognosis and predicts a positive response to hormonal therapy, but it has not proved to be sufficient as a predictive biomarker for routine evaluation of breast cancer. 9 Thus, PGR and TFF1 may be modestly useful

IFN-g-induced expression of PD-L1 was impaired in LKB1-loss and LKB1-mutant groups (A549-LV-control and A549-LV-KD), and the key vulnerability lies in decreased phosphorylated STAT1 expression and its transcriptional activity. Mass spectrometry (MS) and subsequent CO-IP showed that LKB1 interacted with PARP1 and decreased the catalytic activity of PARP1. Upon IFNg simulation, PARP1 poly (ADPribosyl)ated STAT1 and subsequently inhibited STAT1 phosphorylation, which thereby impaired PD-L1 expression in LKB1 deficient cells. However, PARP1 knockdown or inhibitors decreased poly (ADP-ribosyl)ation of STAT1 and enhanced its phosphorylated level, thus increased the expression of PD-L1, in an IFNg dependent manner. Administering PARP1 inhibitors in synergistic mouse models (LLC-shLkb1) slowed tumor growth and induced a favorable immune microenvironment by upregulating PD-L1 expression on tumor cells and increasing infiltration of CD8 + T cells. Conclusion: Our research revealed that PARP1-mediated poly (ADP-ribosyl)ation of STAT1 as the key step in obstructing IFNg-induced transcription of PD-L1 in LKB1 deficient cells. PARP1 inhibitors can specifically reverse this abnormal state, both in vitro and in vivo. These findings might provide rationales for the combination of PARP inhibitors and anti-PD-1 antibodies in LKB1 mutant lung cancer patients.

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