Highlights d First deep proteogenomic landscape of non-smoking lung adenocarcinoma in East Asia d Identified age, sex-related endogenous, and environmental carcinogen mutagenic processes d Proteome-informed classification distinguished clinical features within early stages d Protein networks identified tumorigenesis hallmarks, biomarkers, and druggable targets

The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities. IntroductionThe association between estrogen and breast cancer was recognized over 100 years ago. Estrogen exerts its function through its 2 nuclear receptors, estrogen receptor α (ERα) and ERβ (1, 2). ER belongs to a superfamily of ligand-activated transcription factors that share structural similarity characterized by several functional domains. N-terminal estrogen-independent and C-terminal estrogen-dependent activation function domains (AF1 and AF2, respectively) contribute to the transcriptional activity of the 2 receptors. The DNAbinding domain of the ERs is centrally located. The ligand-binding domain, overlapping AF2, shows 58% homology between ERα and ERβ. The DNA-binding domain is identical between the 2 receptors, except for 3 amino acids. However, the AF1 domain of ERβ has only 28% homology with that of ERα. The binding of estrogen to ER leads to ER dimerization and its recruitment to the estrogenresponsive elements (EREs) on the promoters of ER target genes, thereby either enhancing or repressing gene activation.The development of breast cancer is associated with dysregulation of ER expression (3-8). Compared with that in normal breast tissues, the proportion of cells expressing ERα is increased, whereas ERβ expression is reduced, in hormone-dependent breast tumors. The ratio of ERα/ERβ expression is higher in breast tumors than in normal tissues, and ERα and ERβ are antagonistic to each other. ERα mediates the tumor-promoting effects of estrogens, whereas ERβ inhibits breast cancer cell growth. ERβ reduces cell proliferation induced by ERα activation. Although ERα and ERβ have been shown to have a yin-yang relationship in breast tumorige...

Four and a half LIM protein 1 (FHL1) belongs to the Lin-1, Isl-1 and Mec-3 (LIM)-only protein family and plays important roles in muscle growth and carcinogenesis. However, the biological function of FHL1 remains largely unknown. Here, we show that FHL1 physically and functionally interacted with oestrogen receptors (ERs), which are involved in breast cancer development and progression. FHL1 bound specifically to the activation function-1 domain of ER. Physical interaction of FHL1 and ER is required for FHL1 repression of oestrogen-responsive gene transcription. FHL1 affected recruitment of ER to an oestrogen-responsive promoter and ER binding to an oestrogen-responsive element. Overexpression of FHL1 in breast cancer cells decreased expression of oestrogen-responsive proteins, whereas knockdown of endogenous FHL1 with FHL1 small interfering RNA increased the expression of these proteins. Further analysis of 46 breast cancer samples showed that FHL1 expression negatively associated with oestrogen-responsive gene expression in breast cancer cells. FHL1 inhibited anchorage-dependent and -independent breast cancer cell growth. These results suggest that FHL1 may play an important role in ER signalling as well as breast cancer cell growth regulation.

Intravenous arsenic trioxide (ATO) has been adopted as the first‐line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar‐Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As4S4, has been shown to be highly effective in treating adult APL. In the treatment of pediatric APL, the safety and efficacy of RIF remains to be confirmed. This randomized, multicenter, and noninferiority trial was conducted to determine whether intravenous ATO can be substituted by oral RIF in the treatment of pediatric APL. From September 2011 to January 2017, among 92 patients who were 16 years old or younger with newly diagnosed PML‐RARa positive APL, 82 met eligible criteria and were randomly assigned to ATO (n = 42) or RIF (n = 40) group. The remaining 10 patients did not fulfilled eligible criteria because five did not accept randomization, four died and one had hemiplegia prior to arsenic randomization due to intracranial hemorrhage or cerebral thrombosis. Induction and consolidation treatment contained ATO or RIF, all‐trans‐retinoic acid and low intensity chemotherapy. End points included event‐free survival (EFS), adverse events and hospital days. After a median 3‐year follow‐up, the estimated 5‐year EFS was 100% in both groups, and adverse events were mild. However, patients in the RIF group had significantly less hospital stay than those in the ATO group. This interim analysis shows that oral RIF is as effective and safe as intravenous ATO for the treatment of pediatric APL, with the advantage of reducing hospital stay. Final trial analysis will reveal mature outcome data.

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