William W. Young, Jr. Ph.D.

This grant is being fully funded by the Thomas G. Labrecque Foundation, through the Joan’s Legacy Grant Program.

Lay Description

Lung cancer is the leading cause of cancer deaths for men and women. The higher frequency of lung adenocarcinoma in women than in men, in both smokers and non-smokers, suggests that gender-dependent factors are part of the causes of lung cancer. The long-term goal of the proposed research is to determine the mechanism(s) responsible for this gender bias for lung adenocarcinoma in women.

The action of female hormones, estrogens, is mediated by proteins called estrogen receptors (ER) inside cells. Mucins are large proteins found on cell surfaces that sense the environment outside the cell and transmit signals about the environment to the inside of the cell. Our proposal is based on three findings. Recently one of these mucins, called MUC1, was shown to bind to ER and to increase the activity of ER. Second, a report published this year by our collaborators found that although lung cancer cells from men and women both contain the same amount of ER, only in lung cancer cells from women does exposure to estrogen stimulate the cells to grow. Because uncontrolled growth is a characteristic of cancer cells, these latter results suggested that ER may be involved in the gender bias for lung adenocarcinoma. Third, our laboratory has found that there is a difference in the frequency of two forms of MUC1 in lung carcinoma cells from women as compared to cells from men.

We propose that those different frequencies of MUC1 forms, if confirmed by testing a larger number of tumors, may be useful for predicting which persons may be more or less susceptible to developing lung adenocarcinoma. We also propose to characterize the relationship between ER and MUC1 in order to determine if the interaction of these two key proteins may be involved in the gender bias for lung adenocarcinoma in women.

Scientific Abstract

Lung Cancer is the leading cause of cancer deaths for men and women. The higher frequency of lung adenocarcinoma in women than in men, in both smokers and non-smokers, suggests the involvement of gender-dependent factors in lung cancer etiology. The long term goal of the proposed research is to determine the mechanism(s) responsible for this gender bias for lung adenocarcinoma in women.

This proposal focuses on two topics: splice variants of the mucin MUC1 as biomarkers for lung adenocarcinoma; and interactions between MUC1 and estrogen receptors that may affect susceptibility of men and women to lung adenocarcinoma.

This proposal is based on three findings from 2006: [1] MUC1 binds to, stabilizes, and increases the transcriptional activity of estrogen receptor alpha (ER?) (1); [2] our collaborators reported that although adenocarcinoma cells from both male and female patients expressed ER?? and ER?, estradiol stimulated proliferation only in cells from females (2); and [3] our preliminary results indicate an unexpectedly low frequency of the MUC1/A splice variant in lung adenocarcinoma tumors and tumor cell lines from male patients and a similarly low frequency of the MUC1/B variant in tumor cells from female patients. These data suggest that MUC1/A and MUC1/B may represent biomarkers for gender-specific susceptibility to lung adenocarcinoma. Therefore, the goals of this project are to determine: if the gender differences of MUC1/A and MUC1/B frequencies can be used for risk assessment of lung adenocarcinoma; and if interactions between MUC1 and ER affect lung cancer susceptibility.

The hypothesis of this project is that these gender-specific differences in susceptibility to lung adenocarcinoma are related to interactions between ER and MUC1 and reflect the genetics of MUC1 splicing. Two specific aims will be investigated. Aim 1 will characterize the MUC1/A and MUC1/B splice pattern in lung adenocarcinoma. Additional tumor samples will be analyzed to confirm that the splice pattern differences are of statistical significance. Five year survival data will be used to determine if the splice variant pattern correlates with survival. Also, we will determine if the gender-specific splice variant difference correlates with the status of an associated SNP (rs4072037) and/or the size of the MUC1 tandem repeat region. The results of this aim may establish MUC1/A and MUC1/B splice variants as biomarkers for susceptibility to lung adenocarcinoma. Aim 2 will characterize the interactions between estrogen receptors and MUC1. We will determine if MUC1 interacts with both ER? and ER? in both male and female lung adenocarcinoma cells and then determine if there is a difference in the ability of the MUC1/A and MUC1/B splice variants to interact with ER.

The successful outcome of this project may lead to the development of therapies based upon clinical modulation of MUC1 expression.

References:
1. Wei XL, Xu H, Kufe D. MUC1 oncoprotein stabilizes and activates estrogen receptor alpha. Molecular Cell 2006; 21:295-305.
2. Dougherty SM, Mazhawidza W, Bohn AR, Robinson KA, Mattingly KA, Blankenship KA, Huff MO, McGregor WG, Klinge CM. Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer 2006; 13:113-34.