Elevated Neurotensin Level May Predict Breast Cancer in Women

Karla M. Gonye, MBA President, sphingotec LLC Cambridge, MassachusettsMedicalResearch.com Interview with:
Karla M. Gonye, MBA
President, Sphingotec LLC
Cambridge, Massachusetts

MedicalResearch: What is the background for this study?

  • In experimental studies, Neurotensin and neurotensin expression was highly associated to breast cancer tissue
    • Dupouy et al (2009) investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal carcinomas (IDCs) and found that NTS is expressed in ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade 3 (p<0.05), larger tumor size (p<0.01), and the number of metastatic lymph nodes (p<0.05).
    • It was concluded from this paper that NTS/NTSR1 is a contributor to breast cancer progression.
    • Souaze et al (2006)also studied IDCs and found 34% of all tumors were positive for neurotensin and 91% positive for the NT1 receptor, suggesting the contribution of neurotensin’s involvement in the signaling cascade within breast cancer progression.  In this study, it was found that disruption of neurotensin receptor signaling by silencing RNA or using a specific NT1 antagonist in nude mice xenografted with an aggressive cell line SR48692, caused the reversion of transforming functions that lead to tumor growth.
    • These findings support the contribution of neurotensin to breast cancer progression.
    • Wu, Z. et al (2013) reviewed the contribution of the neurotensinergic system to cancer progression, as well as the regulation and mechanisms of the system in order to highlight its potential as a therapeutic target, and its prospect for its use as a treatment in certain cancers.
    • This summarizes nicely the oncogenic effects of neurotensin after stimulation signaling proliferation, survival, migration, invasion and neoangeogeneis.
    • Several other papers published demonstrate the effects of neurotensin in cancers including breast cancer.
    • New studies such as Roselli et al (2015) further demonstrate the role of neurotensin in aggressive breast cancer.
    • At sphingotec, it was hypothesized that disease progression begins earlier than symptoms are present and that elevated expression of neurotensin in the blood would be an indicator of future breast cancer; measurement of this hormone peptide was possible with the company’s expertise, and that test could be developed to precisely measure neurotensin.
    • This method is published in Ernst et al (2006) in Peptides.
    • To test the hypothesis, the first clinical study was conducted in a cohort of normal healthy population that was indentified from the Malmo Diet and Cancer study, a prospective epidemiological study of 28,449 men and women. Of this group, a subset of 4632 randomly selected subjects were identified and neurotensin was measured in all subjects. Subjects were adjusted for known breast cancer risk factors such as age, age of menarche, heredity of cancer (all), hormone status, etc. (see Table 3, Melander et al JAMA 2012) so that the factors did not influence outcomes. On a 10-15 follow up period, of these subjects, 123 breast cancer events were found to be associated with higher levels of neurotensin, with the highest quartile associated with the highest levels of neurotensin and the lowest quartile associated with the lowest levels of neurotensin. The association of elevated neurotensin was found to be statistically significant for prediction of breast cancer.

MedicalResearch: What are the main findings?


  • Elevated neurotensin levels were associated with breast cancer.
  • Each SD increase of proneurotensin was associated with an HR of 1.44 (95% CI, 1.21-1.71) for the risk of future breast cancer, and the top vs. bottom quartiles of proneurotensin were associated with an HR of 2.44 (95% CI, 1.44-4.15) for risk of breast cancer (Table 3).
  • Elevated neurotensin was also associated with diabetes and cardiovascular disease, mediated through the NTSR3/SORT1 gene in individuals with a genetic variant; however the strongest overall association was with breast cancer
  • The association was seen in women not men.

The findings in the Malmo Diet and Cancer study were later validated in a separate and independent cohort known as the Malmo Prevention Project (MPP). This was another epidemiological cohort of 18,449 men and women in which a case control study was conducted to compare 130 subjects with breast cancer to a group of 1439 subjects without breast cancer. The subjects with breast cancer had significantly higher neurotensin levels. Results conclude that: Proneurotensin [odds ratio (OR) per standard deviation (SD) increment of LN-transformed proneurotensin] was significantly related to incident breast cancer [OR, 2.09; 95% confidence interval (CI), 1.79–2.44; P < 0.001; adjusted for age, body mass index (BMI), smoking, and hormone replacement therapy].

The main difference between MDC and MPP was that the age group in MPP was about 10 years older than MDC and the follow up time was shorter.

MedicalResearch: What should clinicians and patients take away from your report?

  • Neurotensin is an independent risk predictor of future breast cancer in women without a family history of the disease.
  • When put in the context of other known risk factors that clinicians utilize today to counsel patients, such as age, smoking, age of menarche, menopausal status, a proneurotensin level is a much stronger and independent predictor of future breast cancer particularly in the group of women do not have a family history of breast cancer
  • Understanding factors related to disease progression can allow a woman and her clinician to understand her risk and allow for interventions. Such interventions may be to control modifiable risk factors
  • Given the annual incidence of breast cancer, clinicians should be eager and excited to learn what more they can do identify women at highest risk women for breast cancer and discuss treatment/interventions with their patients.

MedicalResearch: What recommendations do you have for future research as a result of this study?


  1. Combination of pro-NT and pro-ENK – do they combined improve risk prediction? In process
  2. How do these two biomarkers perform in women with family history (BRCA 1/2 mutation) taken into account – does it add to risk prediction? In process
  3. How do these two biomarkers perform in women on Hormone Replacement Therapy – can patients be reclassified into different risk categories? In process
  4. How do these two biomarkers perform in different ethnic groups – US, African American, Hispanic, Asian American In process
  5. What are interventional strategies that can be used to reduce pro-neurotensin levels and increase pro-enkephalin levels as a way to reduce breast cancer risk? In process
  6. How can these biomarkers be incorporated to improve other risk models such as GAIL, Tyrer-Cuzick, BRCApro, others? Planning
  7. Can pro-NT/pro-ENK be used to identify women at highest risk to guide HRT, more intensive screening – Ultrasound, MRI, Tomosynthesis?
  8. Can pro-ENT/pro-ENK be used to guide Tamoxifen use?


Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1672-6. doi: 10.1158/1055-9965.EPI-13-1200. Epub 2014 Jun 12.

Validation of plasma proneurotensin as a novel biomarker for the prediction of incident breast cancer.

Melander O1, Belting M2, Manjer J3, Maisel AS4, Hedblad B5, Engström G6, Nilsson P5,Struck J7, Hartmann O7, Bergmann A8, Orho-Melander M6.

Karla M. Gonye, MBA (2015). Elevated Neurotensin Level May Predict Breast Cancer in Women 

[wysija_form id=”5″]