Elsevier

Seminars in Oncology

Volume 41, Issue 1, February 2014, Pages 5-16
Seminars in Oncology

Estrogenic Steroid Hormones in Lung Cancer

https://doi.org/10.1053/j.seminoncol.2013.12.009Get rights and content

It is becoming increasingly clear that steroid hormones are involved in the biology of many organs outside the reproductive system. Evidence has been accumulating since the mid 1990s that the lung contains receptors for both estrogen and progesterone and that these hormones have some role in lung development, pulmonary inflammation, and lung cancer. The estrogen receptor β (ERβ) is the major ER expressed in lung tissues, while inflammatory cells capable of infiltrating the lung are reported to express both ERα and ERβ. Although there is evidence in animals of preferential effects of ERβ in the lungs of females, human lung tumors from males also contain ERβ-positive cells and express aromatase, the enzyme that converts testosterone to estrogens. This review will discuss current literature findings on the role of the ERs and the progesterone receptor (PR), as well CYP19 (aromatase), the rate-limiting enzyme in the synthesis of estrogen, in lung cancer.

Section snippets

ERs and Lung Cancer Survival

There are now many published reports examining ER status in relation to NSCLC patient survival (Table 1). Recently, high cytoplasmic ERβ-1 staining was identified as a negative prognostic factor for lung cancer, independent of other prognostic factors.22 Nuclear ERβ positivity was observed in the majority of lung cancer cases13, 14, 15, 16, 22 and was found to be a favorable prognostic indicator in some studies. In some reports, the prognostic significance was only observed in male patients or

Hormone Replacement and Lung Cancer Survival

Exposure to hormone replacement therapy (HRT) has negative effects on lung cancer survival. Ganti et al31 reported that a significant association between both a lower median age at lung cancer diagnosis and a shorter median survival time in women who used HRT around the time of diagnosis versus those who did not. This effect was more apparent in women who smoked, suggesting an interaction between estrogens and tobacco carcinogens. The Women’s Health Initiative, a randomized, placebo-controlled

Aromatase in Lung Cancer

CYP19, otherwise known as aromatase, a member of the cytochrome P450 family, catalyzes the conversion of androstenedione and testosterone to estrone and β-estradiol, respectively, and both CYP19 mRNA and protein have been detected in the lung.41, 42 High β-estradiol levels were detected by mass spectroscopy in intratumoral extracts of primary NSCLC.43 Several studies have now shown the ability of lung cancer cells to synthesize their own estrogen. Aromatase protein was expressed in NSCLC cell

Non-Genomic Estrogen Signaling and Interactions with Growth Factor Receptor Signaling Pathways

Although most breast cancer studies focus on nuclear actions of ERs, involving changes in gene transcription that take place over several hours or longer through direct binding of ERs to promoter elements of estrogen response genes, estrogen also can rapidly activate cytoplasmic kinase signaling in seconds to minutes. This rapid signaling is termed non-genomic and occurs via non-nuclear ERs located in the membrane or the cytoplasm. In breast cancer cells, an additional membrane ER was

Prs in Lung Cancer

There are two major isoforms of PR, PR-A and PR-B, which play different roles in modulating cellular responses to progesterone. PR is an estrogen response gene, and PR-positive breast cancers are usually more differentiated tumors that respond to anti-estrogen therapy. The ratio of PR-A to PR-B is thought to affect clinical outcome for breast cancer, with high levels of PR-A associating with more differentiation and better survival. There are several reports of expression of total PR by primary

ERs in Other Nonreproductive Malignancies

Expression of ER has been observed in tumors derived from other non-endocrine target tissues, such as head and neck squamous cell carcinoma (HNSCC). HNSCC tumors express ERs, although with variable results reported in the literature. Exogenous estrogen has been shown to stimulate HNSCC proliferation and invasion in vitro77 and to increase tumor growth in mice.78 Similar to lung cancer, estrogen has been shown to induce both genomic (transcriptional responses) as well as non-genomic (rapid

Summary

Research on steroid hormones in lung cancer is likely to benefit both men and women. Lung cancer in both male and female patients is ER- and PR-positive, as well as often being aromatase-positive. Cell lines derived from both sexes are responsive to estrogens, and show responses to therapeutic agents targeting the estrogen pathway. Endocrine-based therapeutic treatments may therefore be beneficial for both men and women. Endocrine therapies also have potential for lung cancer prevention.

Acknowledgments

This work was supported in part by the following grants: SPORE in Lung Cancer P50 090440 from the National Cancer Institute to J.M.S., Career Development Award from the SPORE in Lung Cancer P50 090440 to L.P.S., an award from the V Foundation for Cancer Research to J.M.S., and an award from the Lung Cancer Research Foundation to L.P.S.

The authors thank Carmella Campbell for assistance in preparation of the manuscript.

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