Affiliations of authors: X. Hu, M. P. Cleary, The Hormel Institute, University of Minnesota, Austin, MN; S. C. Juneja, N. J. Maihle, Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
Correspondence to: Margot P. Cleary, PhD, The Hormel Institute, University of Minnesota, 801 16th Ave., NE, Austin, MN 55912 (e-mail: mpcleary{at}hi.umn.edu).
The correspondence from Oelmann et al. regarding our study suggests that our literature review and results will be interpreted to indicate that leptin promotes generalized tumor growth and this will affect clinical practice. They base their concern on their observations that leptin did not promote colony formation in a variety of transformed cell lines including the two breast cancer cell lines HTB26 and HTB131. We respond by addressing the following three points: 1) methodological concerns, 2) characteristics of breast cancer cell lines, and 3) potential clinical applications.
First, there are differences in the anchorage-independent growth assays used in our study and the study presented by Oelmann et al. Total lack of responsiveness of any cell line (to leptin) in their study is impressive, but it is unclear whether they included a positive control such as epidermal growth factor in their study. Their assay primarily has been used to assess inhibition of colony formation. In addition, although they indicated that this assay reflects tumorigenesis in vivo, there appears to be only one previous example comparing a decrease in colony formation with tumor prevention in nude mice (1).
Second, in our study we used the estrogen receptor-positive breast cancer cell line T-47D and the nonmalignant breast cell line HBL 100. Both cell lines express OB-Rb, and in the presence of exogenous leptin demonstrated activation of leptin-dependent signaling pathways and increased cell proliferation. However, only T-47D cells exhibited enhanced colony formation in response to the addition of leptin. The two breast cancer cell lines used by Oelmann et al. are estrogen receptor-negative. Interestingly, elevated body mass index (BMI = weight [kg]/height [m2]) is usually associated with hormone-responsive tumors (24). Additional support for a role for leptin in the development of hormone responsive breast/mammary tumors has been obtained from rodent studies. Mammary tumor development does not occur in either leptin-deficient (5) or leptin receptor-deficient (Cleary, M. P., Grande, J. P., Maihle, N. J.; unpublished data) murine mammary tumor virus-transforming growth factor (MMTV-TGF-
) mice. MMTV-TGF-
mice overexpress human TGF-
gene and leptin-sufficient mice exhibit a 50% or greater incidence of mammary tumors by 104 weeks of age (5) (Cleary, M. P., Grande, J. P., and Maihle, N. J., unpublished data). Furthermore, MMTV-TGF-
mice with diet-induced obesity have a shortened latency for mammary tumor development (Cleary, M. P., Grande, J. P., and Maihle, N. J., unpublished data). Although serum leptin levels were not measured in these mice, a more recent study indicates that serum leptin levels are elevated in this obesity model (Hu, X, Juneja, S. C., Grande, J. P. Maihle, N. J., and Cleary, M. P., unpublished data). Collectively, these studies suggest that women with elevated body weight and/or elevated serum leptin levels may be at risk for hormone-responsive tumors.
The last point we wish to address is the potential clinical use of leptin. In this report, we made no recommendations for clinical application(s). However, from our results and those of others, particularly for malignancies associated with being overweight and obese, additional studies on effects of leptin on tumor development seem warranted. Currently, there are few epidemiologic studies addressing the role of leptin in human cancers. No definitive results have been reported documenting an association between serum/tissue leptin levels and breast cancer; however, given the small sample sizes and the inclusion of premenopausal women, this result is perhaps not surprising. However, Tessitore et al. (6) have reported higher serum leptin levels in women with breast cancer (compared with control subjects matched for BMI), and other results support a role for leptin in prostate cancer, another hormone-responsive malignancy (7). Thus, continued studies at the cellular, animal model, epidemiologic, and clinical levels, particularly for malignancies associated with being overweight and obese, should continue to provide evidence to further implicate or absolve leptin as an etiologic factor in the development of various malignancies, including breast cancer.
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