Macrophages in Breast Cancer Patients of African Descent

Institution: University of California, San Francisco
Investigator(s): Rita Mukhtar, M.D. -
Award Cycle: 2009 (Cycle 15) Grant #: 15FB-0108 Award: $89,518
Award Type: Postdoctoral Fellowship
Research Priorities
Community Impact of Breast Cancer>Disparities: eliminating the unequal burden of breast cancer

Initial Award Abstract (2009)

The normal immune system employs cells called macrophages to function against both infection and various types of inflammation. In response to proteins called cytokines, macrophages produce angiogenic and stromal breakdown factors, both of which are beneficial in certain settings, such as wound healing. However, a large body of research now shows that many cancer cells can attract macrophages, subverting their role to facilitate cancer growth and spread via angiogenesis. In fact, examination of breast cancer specimens from women we have treated has shown that high numbers of macrophages predict poor outcomes. Given reports of particularly aggressive breast cancers in Nigerian women, we became interested in looking for macrophages in breast cancer specimens from Nigeria. Subsequently, we found that many more Nigerian breast cancer patients had high levels of tissue macrophages in their cancers than women in the U.S. This intriguing finding implicates macrophages in the pathogenesis of aggressive breast cancers. Other work from our group suggests that high levels of tissue macrophages portend poor prognosis in breast cancer.

Since women of African descent in the U.S. have poor outcomes following diagnoses of breast cancer, even when controlling for factors such as access to health care, we are interested in investigating whether or not these women have higher levels of tissue macrophages compared to other groups. Additionally, we hope to correlate tissue macrophage level with a blood marker. There is now a critical mass of data from in vivo and clinical studies showing that macrophages play a role in the progression and possibly in the development of some breast cancer subtypes. Understanding the role macrophages may shed light on outcomes disparities in the U.S., and lead to new detection techniques and prognostic information. Specifically, we will obtain breast tissue samples from African American women and non-African American women with breast cancer and determine the incidence of high levels of pathogenic tissue macrophages. Next, we will obtain serum samples from breast cancer patients and correlate tissue macrophage levels with blood markers.

This work has the potential to identify an explanation for outcomes disparities in women of African descent in the U.S. Additionally, we hope to identify a blood marker that could be used for detection, prognostic information, and following response to treatment. The ultimate goal would be the identification of patients who could benefit from the use of novel anti-macrophage agents currently in development.

Final Report (2011)

Increasing evidence implicates tumor associated macrophages (TAMs) in the pathogenesis of breast cancer. We previously identified a subpopulation of TAMs expressing proliferating cellular nuclear antigen (PCNA) in patients with highly aggressive breast cancers from Nigeria, and hypothesized that we would find high levels of these PCNA+ TAMs in African American breast cancer patients, a population that continues to have outcomes disparities of unclear origin. We identified a cohort of ethnically diverse breast cancer patients from Alameda County Medical Center (Highland Hospital) and measured levels of PCNA + TAMs. High levels were associated with hormone receptor negative, high grade tumors, which are more likely to be found in African American patients. Interestingly, we found that the entire cohort of patients had high levels of PCNA + TAMS, and that the highest levels were associated with decreased survival. PCNA + TAM levels were highest in women of Hispanic origin, but all non-Caucasian women had higher levels and worse outcomes than Caucasian women.

TAMs are recruited to tumor sites and two contrasting activation states, or phenotypes, are described in the literature: the anti-tumoral M1 phenotype, and the pro-tumoral M2 phenotype. Given our finding that TAMs expressing PCNA are associated with non-Caucasian ethnicity and poor outcomes, we sought to determine whether or not these PCNA+ TAMs are associated with a particular macrophage activation state. Based on literature review, we developed two macrophage gene-sets comprised of 38 M1-related genes and 29 M2-related genes, and an anti-tumor immune response set comprised of 26 cytotoxic T cell and MHC Class II related genes. We hypothesized that PCNA+ TAMs would express high levels ofM2 related genes, and low levels of anti-tumor related genes. We measured levels of PCNA + TAMs in 135 patients with invasive breast cancer from the I-SPY 1 Trial, a prospective, neoadjuvant trial with gene array data available. In contrast to our hypothesis, patients with high levels ofPCNA+ TAMs expressed more M1 related than M2 related genes. Those that had high levels of PCNA+ TAMs and low levels of the anti-tumor immune response (cytotoxic T cell/MHC Class II genes) had the worst outcomes. These results suggest that PCNA+ TAMs represent a heterogeneous mixture of TAMs, some of which may be pro or anti-tumoral. Additionally, their role may differ based on the tumor microenvironment. Future work on this project will include further identification ofPCNA+ TAM subtypes, and the development of serum markers associated with TAMs, a project which is currently ongoing.

Elevated PCNA+ tumor-associated macrophages in breast cancer are associated with early recurrence and non-Caucasian ethnicity.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Mukhtar RA, Moore A, Nseyo O, Baehner F, Au A, Moore D, Twomey P, Campbell M, Esserman L
Yr: 2011 Vol: 130 Nbr: 2 Abs: Pg:635-44

Tumor-associated macrophages in breast cancer as potential biomarkers for new treatments and diagnostics.
Periodical:Expert Reviews Molecular Diagnostics
Index Medicus: Expert Rev Mol Diagn
Authors: Mukhtar RA, Nseyo O, Campbell MJ, Esserman LJ
Yr: 2011 Vol: 11 Nbr: 1 Abs: Pg:91-100