Our laboratory focuses on breast cancer. We currently have three research projects:

Mitochondrial unfolded–protein response

A second area of interest in our laboratory is to understand the role of the mitochondrial heterogeneity in breast cancer progression. Cancer cells are characterized by mutations in both the nuclear and mitochondrial genomes as well as by an oxidative environment. Both of these events can lead to misfolding of proteins and result in proteotoxic stress. While accumulation of misfolded proteins in the cytoplasm can be directly limited by the activity of the 26S proteasome, the presence of misfolded proteins within the lumen of organelles represents an additional challenge. The unfolded protein response (UPR) was first described as the result of accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (UPRER). More recently however, activation of a distinct UPR in response to the accumulation of misfolded proteins in the lumen of the mitochondria (UPRmt) has begun to be appreciated. While advances in the molecular characterization of the UPRmt have been made in C. elegans in the context of its role in the control of longevity.

Our laboratory however focuses specifically on the role of the UPRmt to maintain the integrity of the mitochondrial network in face of oxidative stress during oncogenic transformation in mammalian cells.

We have identified the mitochondrial sirtuin, SIRT3 and the estrogen receptor alpha (ERa) as key players of the UPRmt. Overall, the picture that emerges is that the UPRmt represents a multi-layers response coordinating an array of “mito-protective” outcomes. Given the critical importance of the metabolic reprogramming of the mitochondria in cancer cells, the study of the UPRmt is rapidly gaining more attention. In addition to its growing importance in cancer biology, we recently have obtained evidence that the UPRmt may also play a critical role in the protection against neurodegenerative diseases such as ALS.

In the future, we will continue to explore the role of the UPR in both breast cancer progression and ALS using an array of mouse models of these diseases. Further, since both SIRT3 and estrogen are associated with longevity, we have a kin interest in understanding the link between aging and the increased risk of developing these diseases.

Pregnancy-associated breast cancer

One area of interest that we are currently pursuing is the link between pregnancy and breast cancer. Pregnancy at a young age (before the age of 25) is associated with a reduction in the overall life-time risk of developing breast cancer. This observation represents the protective effect of pregnancy. However, pregnancy is also associated with a transient increase in risk of breast cancer in all women, which peaks at 6 years after pregnancy. Further, the risk increases with the age of the mother at first pregnancy. Since women in developed countries tend to have children after the age of 30, pregnancy represents an important etiological factor in breast cancer today.

The current definition of pregnancy-associated breast cancer (PABC) is empirically limited to breast cancers arising within 2 years of pregnancy. The 15-year survival of women diagnosed with breast cancer 1 and 2 years after giving birth is 38% and 51%, respectively, compared to 65% in age-matched nulliparous women, suggesting the aggressive nature of the disease. The restricted time frame of diagnosis allowed by the current definition fuels the notion that PABC is a rare phenomenon. However, since the epidemiological data demonstrate that the increase in risk peaks 6 years following pregnancy, PABC arising beyond the 1 to 2 year window may represent the vast majority of cases. If so, PABC may represent a considerable fraction of breast cancers.

One major breakthrough regarding PABC is the discovery that involution of the breast following pregnancy is tumorigenic. Work in our laboratory has identified the protease Pappalysin-1 (PAPP-A) as a involution-dependent oncogene as it is activated specifically during involution. PAPP-A cleaves the inhibitors of IGF signaling IGFBP-4 and 5. We found that expression of PAPP-A increases the deposition of collagen during involution and that collagen enhances the ability of PAPP-A to cleave its substrates therefore establishing a positive feedback loop. We also found that lactation opposes the oncogenic function of PAPP-A.

This observation is in line with a large analysis of the effect of breastfeeding using combined results from 47 studies, involving a total of 50,302 women, revealed that extended lactation is protective against breast cancer. This study suggested that the cumulative risk of breast cancer could be reduced by half should the period of breastfeeding be increased. In addition, breastfeeding was found to be protective against more aggressive tumors, but the mediators of the protective effect of lactation have not been identified.

In the future, we aim at further understanding the role of breastfeeding on the oncogenic function of PAPP-A–driven PABC. Further, we are interested in exploring the possibility that altered collagen in an aging breast may favor the oncogenic function of PAPP-A.

Developing novel strategies to improve endocrine therapy of breast cancer: Bench to clinic

A third long standing area of interest in our laboratory is the development of improved therapeutic strategies to target the ERa in breast cancer. Our past effort has led to the discovery that the proteasome inhibitor Bortezomib can enhance the efficacy of the anti-estrogen receptor drug fulvestrant. This work has led to a large phase II randomized clinical trial in post-menopausal women with metastatic breast cancer. The results of this trial revealed the superiority of the fulvestrant-bortezomib combinationover the fulvestrant alone and suggests that the combination delays acquired resistance to fulvestrant.

We currently are initiating a pre-operative clinical trial in premenopausal women to compare the efficacy of tamoxifen and fulvestrant based on data obtained in our laboratory suggesting that cyclin D1 can act as a biomarker to better orient the use of these drugs. Our data suggests that the cdk-dependent and independent roles of cyclin D1 in the regulation of the ERa are critical in targeting these drugs in the clinic.

In the future, our goal is to design clinical trials specifically against pregnancy-associated breast cancers. We are also working toward the goal of targeting the UPRmt for therapy.

For more information please visit our website at:

http://labs.icahn.mssm.edu/germainlab/