## 1 Introduction
This activity of estrogen was noted as dependent on a half-estrogen-response element apart from an activator protein (AP-1) site residing within this enhancer. The conservation of this AP-1 binding site in 11 distinct mammalian species and active estrogen-AP-1 jointly suggestsAP-1 as the source to propagate the tumor development. Exclusive involvement of AP-1 in this tumor-promoting activity was confirmed by small interfering RNA experiments and chromatin immunoprecipitation assays wherein estrogen receptor-AP-1 cross-talk was demonstrated as an essential factor to induce c-myc expression [81]. Noted human lung cancer cell lines are characterized by the generation of multiple growth factors that are engaged in proliferation via paracrine and autocrine loops through specific receptors. The resultant products from some activated proto-oncogenes (c-sis and c-erbB-2) are the homologous sequences to some specific growth factor (such as platelet-derived growth factor (PDGF)) and the EGFR, commonly identified in lung cancer. Actions of these growth factors serve as decisive links for tumor progression via intracellular signal transduction and specific oncogenic activation. The observations of a 1990 study mention the presence of fur gene in 32 of the 40 NSCLC examined biopsies [82]. The fur gene encodes for a membrane-associated protein, and its involvement in NSCLC development is due to its location immediately upstream of the fes/fps proto-oncogene. With its receptor-like attributes, the fur gene together with fes/fps proto-oncogene exhibits a tyrosine protein kinase activity, which draws significance from the therapeutic rationale of using selective tyrosine kinase inhibitors of EGFRs, whose overexpression remains a recognized hallmark of NSCLC [83]. The above 1990 investigation examined c-erbB-2 expression in 60 patients (SCLC and NSCLC both) along with 11 lung cancer cell lines. The product from c-erbB-2 is a membrane protein having tyrosine kinase activity with c-erbB-2 having a sequence homology with EGF receptor. The gene for c-erbB-2 was mapped to chromosome 17 (17q21) wherein only two of the 60 examined biopsies exhibited amplification. Interestingly, all the seven investigated NSCLC cell lines showed an increased c-erbB-2 gene expression with a characteristically high transcription extent compared to the SCLC cell lines. With a sequence homology of EGF receptor, for which the estrogenic activity is well-known for aggravating tumorigenesis via EGFR signaling, the c-erbB-2 gene presents a high likelihood of being intercepted by estrogen for an enhanced carcinogenic response. A different study noticed enhanced c-erbB-2 proto-oncogene expression in squamous and large-cell undifferentiated cancers contrary to the adenocarcinoma. Encoding a growth factor receptor on glandular epithelium, this gene is implicitly amplified only in an adenocarcinoma. Abnormal expression of this gene is noticed at a higher rate in advanced than early-stage cancers [84]. This investigation studied the expressions of c-myc, c-myb, c-ras-Ha, c-erbB-1 and c-erb-B-2 proto-oncogenes in NSCLC and observed their detectable abnormalities in adenocarcinoma (ten out of sixteen) and large-cell cancers (two out of two). The c-sis oncogene in the same study [83] was noticed as prevailing homologous to platelet-derived growth factor (B-chain), expressed in five of the six examined NSCLC cell lines. Transcripts for PDGF A-chain were detected in all studied six NSCLC cell lines. The transforming growth factors (TGFs) \(\alpha\) and \(\beta\) were positive in four and five NSCLC cell lines. Injection of studied NSCLC cell lines into nude mice revealed varying extents of collagen-rich tumor stroma, suggesting a paracrine functioning of PDGF and TGF in NSCLC cell lines. Here again, five of the studied six NSCLC cell lines possessed EGF receptor transcripts. Thereby, a significant association of c-erbB-2, c-sis and c-fes with EGFR expression infers an aggravated NSCLC carcinogenesis via ER-EGFR interactions.