Short summary

Mammary adipose tissue is found adjacent to cancer cells and secretes various factors that promote tumor development. This project aims to investigate two potential key players in this adipocyte-cancer cell crosstalk; IGF-2 and PAPP-A. The proteins will be assessed in adipose tissue from patients with breast cancer and in cell culture models that mimic conditions in breast cancer. Finally, the proteins will be investigated in relation to patient BMI to study the link between cancer and obesity.

Rationale

There is a growing appreciation for the link between breast cancer and obesity. Mammary adipose tissue is found adjacent to cancer cells and secretes various factors that promote tumor development.

A potential key player in this adipocyte-cancer cell crosstalk is the enzyme pregnancy-associated plasma protein-A (PAPP-A). PAPP-A stimulates local actions within the tissues of the insulin-like growth factors (IGFs). Especially IGF-2 is of interest in cancer. IGF-2 has high affinity for the insulin receptor subtype A (IR-A), and both its activator, PAPP-A, and its receptor, the IR-A, are expressed by a wide range of malignant cells and play key roles in the hallmarks of tumor progression. Of note, IR-A expression is dominant in breast cancer tissues, where it mediates a mitogenic signal - yet till now its activation by IGF-2 has received surprisingly little attention.

Recently, we demonstrated that IGF-2 and PAPP-A are produced in high amounts by human adipose tissue, and that elevated serum PAPP-A levels predict relapse of breast cancer. In addition, PAPP-A was remarkably stimulated by pro-inflammatory proteins, which are abundant in cancer tissues. In light of the above, we envisage that PAPP-A and IGF-2 are secreted from mammary adipose tissues adjacent to breast cancer cells and are able to promote cancer growth though activation of the IR-A. If so, this crosstalk could likely be amplified in obese patients, thus explaining in part the excess occurrence of breast cancer in obese women. Our hypotheses will be tested by developing novel analyses and cell culture models that mimic conditions in breast cancer.

Furthermore, we will use mammary adipose tissue from breast cancer patients to study if cancer cells are jointly stimulated by PAPP-A and IGF-2 produced by adipocytes. Using tissue samples from a large cohort of breast cancer patients, we will assess the expression levels of PAPP-A, IGF-2 and IR-A in adipose tissue in relation to cancer subtype and prognosis. Finally, we will test the hypothesis that local inflammation in the adipose tissue potentiates the vicious signaling, hereby driving cancer progression.

This project hopes to improve the understanding of PAPP-A and IGF-2 as key partakers in cancer development and to explain why obesity is associated with breast cancer. Neutralizing antibodies against PAPP-A are currently under development, and thus, our results may ultimately pave the way for new anti-neoplastic treatment in humans.

Description of the cohort

Mammary adipose tissue and tumor samples will be collected from women undergoing breast cancer surgery (mastectomy) at the department of plastic surgery, OUH, and the Department of Pathology, OUH. Patients will be selected based on BMI; BMI<25 and BMI>30

Data and biological material

Adipose and cancer tissue. Data from patient journals.

Collaborating researchers and departments

Department of Plastic Surgery, OUH

• Katrine Lydolph Søe

Department of Pathology, OUH

• Anne Marie Bak Jylling

Department of Oncology, Aarhus University Hospital

• Signe Borgquist

Oncology and Pathology, Lund University

• Ann Rosendahl